Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle kinase mediated cellular proliferation

ABSTRACT

This invention relates to the inhibition of protein tyrosine kinase (PTK) and cell cycle kinase mediated cellular proliferation. More specifically, this invention relates to naphthyridinones and their use in inhibiting cellular proliferation and PTK or cell cycle kinase enzymatic activity.

This application is a 371 of PCT/US98/16848 filed Aug. 13, 1998 whichclaims the benefit of Provisional 60/056,746 filed Aug. 20, 1997.

FIELD OF THE INVENTION

This invention relates to the inhibition of protein tyrosine kinase(PTK) and cell cycle kinase mediated cellular proliferation. Morespecifically, this invention relates to naphthyridinones and their usein inhibiting cellular proliferation and PTK or cell cycle kinaseenzymatic activity.

BACKGROUND OF THE INVENTION

Many disease states are characterized by the uncontrolled proliferationand differentiation of cells. These disease states encompass a varietyof cell types and maladies such as cancer, atherosclerosis, restenosis,and psoriasis. Growth factor stimulation, autophosphorylation, and thephosphorylation of intracellular protein substrates are importantbiological events in the pathomechanisms of proliferative diseases.

In normal cells, the phosphorylation of tyrosine residues on proteinsubstrates serves a critical function in intracellular growth signalingpathways initiated by stimulated extracellular growth factor receptors.For example, the association of growth factors such as Platelet-DerivedGrowth Factor (PDGF), Fibroblast Growth Factor (FGF), and EpidermalGrowth Factor (EGF) with their respective extracellular receptors,PDGFr, FGFr, and EGFr, activates intracellular tyrosine kinase enzymedomains of these receptors, thereby catalyzing the phosphorylation ofeither intracellular substrates or the receptors themselves. Thephosphorylation of growth factor receptors in response to ligand bindingis known as autophosphorylation.

For example, the EGF receptor has as its two most important ligands EGFand Transforming Growth Factor α, (TGFα). The receptors appear to haveonly minor functions in normal adult humans, but are implicated in thedisease processes of a large portion of all cancers, especially colonand breast cancer. The closely related Erb-B2 and Erb-B3 receptors havea family of Heregulins as their major ligands, and receptoroverexpression and mutation have been unequivocally demonstrated as themajor risk factor in poor prognosis breast cancer.

The proliferation and directed migration of vascular smooth muscle cells(VSMC) are important components in such processes as vascularremodeling, restenosis and atherosclerosis. Platelet-derived growthfactor has been identified as one of the most potent endogenous VSMCmitogens and chemoattractants. Elevated vascular mRNA expression ofPDGF-A and -B chains and PDGF receptors has been observed inballoon-injured rat carotid arteries (J. Cell. Biol.,1990;111:2149-2158). In this injury model, infusion of PDGF also greatlyincreases intimal thickening and migration of VSMC (J. Clin. Invest.,1992;89:507-511). Furthermore, PDGF-neutralizing antibodiessignificantly reduce intimal thickening following balloon injury(Science, 1991;253:1129-1132). Tyrphostin receptor tyrosine kinaseinhibitors which block the PDGF signal transduction pathway have beenshown to inhibit PDGF stimulated receptor tyrosine kinasephosphorylation in vivo in the rat cuff injury model (Drug Develop.Res., 1993;29:158-166).

Both acidic fibroblast growth factor (aFGF) and basic fibroblast growthfactor (bFGF) have many biological activities, including the ability topromote cellular proliferation and differentiation. Direct evidence insupport of FGF involvement in VSMC has been reported by Lindner andReidy (Proc. Natl. Acad. Sci. USA, 88:3739-3743 (1991)), whodemonstrated that the systemic injection of a neutralizing antibodyagainst bFGF prior to balloon angioplasty of rat carotid arteriesinhibited injury-induced medial SMC proliferation by greater than 80%when measured 2 days after injury. It is likely that bFGF released fromdamaged cells is acting in a paracrine manner to induce VSMC growth.Recently, Lindner and Reidy (Cir. Res., 1993;73:589-595) demonstrated anincreased expression of both mRNA for bFGF and FGFR-1 in replicatingVSMCs and endothelium in en face preparations of balloon-injured ratcarotid arteries. The data provides evidence that in injured arteriesthe ligand/receptor system of bFGF and FGFR-1 may be involved in thecontinued proliferative response of VSMCs leading to neointimaformation.

Buchdunger, et al., Proc. Natl. Acad. Sci., 1995;92:2558-2562, reportedthe inhibition of the PDGF signal transduction pathway both in vitro andin vivo by a PDGF receptor tyrosine protein kinase inhibitor. Thecompound showed antitumor activity in tumor models using astrocytomacell lines.

Thus, EGF, PDGF, FGF, and other growth factors play pivotal roles in thepathomechanisms of cellular proliferative diseases such as cancer,atherosclerosis, and restenosis. Upon association with their respectivereceptors, these growth factors stimulate tyrosine kinase activity asone of the initial biochemical events leading to DNA synthesis and celldivision. It thereby follows that compounds which inhibit PTKsassociated with intracellular growth factor signal transduction pathwaysare useful agents for the treatment of cellular proliferative diseases.We have now discovered that certain naphthyridinones inhibit PTKs, andare useful in treating and preventing atherosclerosis, restenosis, andcancer.

The Src family of protein kinases are involved in a number of cellularsignaling pathways. For example, Src is involved in growth factorreceptor signaling; integrin-mediated signaling; T- and B-cellactivation and osteoclast activation. It is known that Src binds toseveral key receptor and nonreceptor tyrosine kinases such as tyrosinekinases containing receptors for PDGF, EGF, HER2/Neu (an oncogene formof EGF), Fibroblast growth factor, focal adhesion kinase, p130 protein,and p68 protein. In addition, pp60c-src has been shown to be involved inthe regulation of DNA synthesis, mitosis, and other cellular activities.

Cell cycle kinases are naturally occurring enzymes involved inregulation of the cell cycle (Meijer L., "Chemical Inhibitors ofCyclin-Dependent Kinases", Progress in Cell Cycle Research,1995;1:351-363). Typical enzymes include the cyclin-dependent kinases(cdk) cdk1, cdk2, cdk4, cdk5, cdk6, and wee-1 kinase. Increased activityor temporally abnormal activation of these kinases has been shown toresult in development of human tumors and other proliferative disorderssuch as restenosis. Compounds that inhibit cdks, either by blocking theinteraction between a cyclin and its kinase partner, or by binding toand inactivating the kinase, cause inhibition of cell proliferation, andare thus useful for treating tumors or other abnormally proliferatingcells.

Several compounds that inhibit cdks have demonstrated both preclinicaland clinical anti-tumor activity. For example, flavopiridol is aflavonoid that has been shown to be a potent inhibitor of several typesof breast and lung cancer cells (Kaur, et al., J. Natl. Cancer Inst.,1992;84:1736-1740; Int. J. Oncol, 1996;9:1143-1168). The compound hasbeen shown to inhibit cdk2 and cdk4. Olomoucine[2-(hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potentinhibitor of cdk2 and cdk5 (Vesely, et al., Eur. J. Biochem.,1994;224:771-786), and has been shown to inhibit proliferation ofapproximately 60 different human tumor cell lines used by the NationalCancer Institute (NCI) to screen for new cancer therapies (Abraham, etal., Biology of the Cell, 1995;83:105-120).

Despite the progress that has been made, the search continues for smallmolecular weight compounds that are orally bioavailable and useful fortreating a wide variety of human tumors and other proliferativedisorders such as restenosis and atherosclerosis.

The present invention provides compounds that inhibit PTKs and cellcycle kinases.

SUMMARY OF THE INVENTION

The present invention provides compounds having the Formula I ##STR1##wherein -- -- -- is absent or a bond;

R¹ is ##STR2## R² is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, or C₅ -C₁₂bicycloalkyl;

each R³ is independently hydrogen or C₁ -C₆ alkyl;

each n is independently 0 to 7; ##STR3## R⁵ is hydrogen, halogen, aryl,substituted aryl, heteroaryl, or substituted heteroaryl, and thepharmaceutically acceptable salts thereof.

In a preferred embodiment of the compounds of Formula I, ##STR4##

In another preferred embodiment, ##STR5## and R⁴ is --O(CH₂)_(n) --X.

In another preferred embodiment, ##STR6##

In another preferred embodiment, ##STR7##

In another preferred embodiment, ##STR8##

In another preferred embodiment, R¹ is --NH--(CH₂)_(n) --N(CH₂ CH₃)₂.

In another preferred embodiment, R⁵ is phenyl or substituted phenyl.

In another preferred embodiment, R⁵ is 2,6-dichlorophenyl.

In another preferred embodiment, R² is methyl.

In another preferred embodiment, R⁵ is 2,6-dichlorophenyl and R² ismethyl.

In another preferred embodiment, the present invention provides thecompounds:

7-amino-3-(2,6-dichlorophenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-dimethylamino-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[2-(diethylamino)ethylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[3-(diethylamino)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[4-(diethylamino)butylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[5-(diethylamino)pentylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-methylpiperazin-1-yl)butylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[5-(4-methylpiperazin-1-yl)pentylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-morpholino)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[3-(imidazol-1-yl)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-(phenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[(4-methoxyphenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[(4-(2-(diethylamino)ethoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-morpholino)butylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-7-[(4-(3-(diethylamino)propoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(4-methylpiperazin-1-yl)phenyl)amino]-1H-[1,6]naphthyridin-2-one;

7-Amino-1H-[1,6]naphthyridin-2-one;

7-Amino-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-Fluoro-1-ethyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-methoxyphenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-phenylamino-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Diethylamino)propoxy)phenylamino]-1-ethyl-1,6-naphthyridin-2-one;

1-Ethyl-7-[4-(2-(4-methylpiperazin-1-yl)ethoxy)phenylamino]-1,6-naphthyridin-2-one;

1-Ethyl-7-[4-(3-(4-methylpiperazin-1-yl)propoxy)phenylamino]-1,6-naphthyridin-2-one;

1-Ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2one;

1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2one;

1-Ethyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-isopropyl-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[I,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]-phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-1Isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-{4-[4-(3-hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-(4-Fluorophenylamino)-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Isopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one,

3-Fluoro-1-methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;p11-Cycloheptyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-(4-fluorophenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-(4-fluorophenylamino)-1-isopropyl-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-(4-fluorophenylamino)-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;

3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-Fluoro-1-isopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclopentyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cyclohexyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Cycloheptyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-(4-fluoro-3-methylphenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-(4-ethoxyphenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-(3-(hydroxymethyl)phenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-methyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(2-(morpholin-4-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(2-(piperidin-1-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(4-(methylpiperazin-1-yl)methyl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-[4-(2-(dimethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]-benzoicacid;

3-(2,6-Dichlorophenyl)-7-[3-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

N-(2-{4-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenoxy}ethyl)-N-ethyl-acetamide;

{4-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenyl}-aceticacid;

3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-fluoro-3-methylphenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-(4-ethoxyphenylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-(3-(hydroxymethyl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(2-(morpholin-4-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(2-(piperidin-1-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(4-(methylpiperazin-1-yl)methyl)phenylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-7-[4-(2-(dimethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]-benzoicacid;

3-(2,6-Dichlorophenyl)-7-[3-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

N-(2-{4-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenoxy}ethyl)-N-ethyl-acetamide;

3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;

{4-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenyl}-aceticacid;

3-(3,5-Dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(3,5-Dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-3-(3,5-dimethoxyphenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-3-(3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(3,5-dimethoxyphenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(3,5-Dimethoxyphenyl)-1-ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;

3-(3,5-Dimethoxyphenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

1-Methyl-3-(2-methyl-3,5-dimethoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

1-Ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-methyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-3-(2,6-dimethyl-3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

3-(2-Chloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(2,6-dimethyl-3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-methyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-ethyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;

1-Methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-phenyl-1H-[1,6]naphthyridin-2-one;

1-Ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-phenyl-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-methyl-3-phenyl-1H-[1,6]naphthyridin-2-one;

7-(4-(Diethylamino)butylamino)-1-ethyl-3-phenyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-phenyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-phenyl-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(thiophen-3-yl)-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(thiophen-3-yl)-1H-[1,6]naphthyridin-2-one;

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(thiophen-2-yl)-1H-[1,6]naphthyridin-2-one;and

7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(thiophen-2-yl)-1H-[1,6]naphthyridin-2-one.

In one preferred embodiment of the compounds of Formula I, -- -- isabsent.

In another preferred embodiment, -- -- -- is a bond.

In another preferred embodiment, R² is --CH₂ CH₃.

In another preferred embodiment, ##STR9## wherein aryl is phenyl andsubstituted aryl is substituted phenyl.

In another preferred embodiment, ##STR10##

In another preferred embodiment,

R⁵ is hydrogen, ##STR11## fluorine, ##STR12##

In still another preferred embodiment,

R¹ is

--NH₂,

--F,

--NH-phenyl,

--NH-substituted phenyl, ##STR13##

In a more preferred embodiment, the present invention provides compoundsof Formula I ##STR14## wherein -- -- -- is a bond or absent;

R¹ is

--NH₂,

--F,

--NH-phenyl,

--NH-substituted phenyl, ##STR15## R⁵ is hydrogen, ##STR16## fluorine##STR17## the pharmaceutically acceptable salts thereof.

Also provided by the present invention is a method of treating cancer,the method comprising administering to a patient having cancer atherapeutically effective amount of a compound of Formula I.

Also provided is a method of treating or preventing atherosclerosis, themethod comprising administering to a patient having atherosclerosis orat risk of having atherosclerosis a therapeutically effective amount ofa compound of Formula I.

Also provided is a method of treating or preventing restenosis, themethod comprising administering to a patient having restenosis or atrisk of having restenosis a therapeutically effective amount of acompound of Formula I.

Also provided is a method of treating psoriasis, the method comprisingadministering to a patient having psoriasis a therapeutically effectiveamount of a compound of Formula I.

Also provided is a method of inhibiting protein tyrosine kinases, themethod comprising administering to a patient in need of protein tyrosinekinase inhibition a protein tyrosine kinase inhibiting amount of acompound of Formula I.

In a preferred embodiment of the method of inhibiting protein tyrosinekinases, the protein tyrosine kinase is c-Src.

In another preferred embodiment, the protein tyrosine kinase in PDGFr.

In another preferred embodiment, the protein tyrosine kinase is FGFr.

Also provided is a method of inhibiting cell cycle kinases, the methodcomprising administering to a patient in need of cell cycle kinaseinhibition a cell cycle kinase inhibiting amount of a compound ofFormula I.

In a preferred embodiment of the method of inhibiting cell cyclekinases, the cell cycle kinase is CDK4, CDK2, or CDK1.

Also provided by the present invention is a pharmaceutical compositionthat comprises a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" means a straight or branched chain hydrocarbon.Representative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term "halogen" includes chlorine, fluorine, bromine, and iodine.

The term "alkenyl" means a branched or straight chain hydrocarbon havingone; or more carbon--carbon double bond.

The term "aryl" means an aromatic hydrocarbon. Representative examplesof aryl groups include phenyl and naphthyl.

The term "heteroatom" includes oxygen, nitrogen, and sulfur.

The term "heteroaryl" means an aryl group wherein one or more carbonatom of the aromatic hydrocarbon has been replaced with a heteroatom.Examples of heteroaryl radicals include, but are not limited to,pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl,pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.

The term "cycloalkyl" means a cyclic hydrocarbon. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The symbol "--" means a bond.

The term "patient" means all animals including humans. Examples ofpatients include humans, cows, dogs, cats, goats, sheep, and pigs.

The term "substituted" means that the base organic radical has one ormore substituents. For example, substituted aryl means an aryl radicalsuch as benzene that has one or more substituents. Substituents include,but are not limited to, halogen, C₁ -C₈ alkyl, --CN, CF₃, --NO₂, --NH₂,--NHC₁ -C₈ alkyl, --N(C₁ -C₈ alkyl)₂, --OC₁ -C₈ alkyl, --OH, ##STR18##

The term "heterocycle" means a cycloalkyl group wherein one, or morecarbon atom is replaced with a heteroatom. Examples of heterocyclesinclude, but are not limited to, pyrrolidinyl, piperidyl, andpiperazinyl.

The term "bicycloalkyl" means a cyclic hydrocarbon having the formula##STR19## wherein each p is independently 1to 4.

Those skilled in the art are easily able to identify patients havingcancer, atherosclerosis, psoriasis, restenosis, or at risk of havingatherosclerosis or restenosis. For example, patients who are at risk ofhaving restenosis include, but are not limited to, patients havingundergone balloon angioplasty or other surgical vascular procedures.

A therapeutically effective amount is an amount of a compound of FormulaI, that when administered to a patient, ameliorates a symptom of thedisease.

The term "cancer" includes, but is not limited to, the followingcancers:

breast;

ovary;

cervix;

prostate;

testis;

esophagus;

glioblastoma;

neuroblastoma;

stomach;

skin, keratoacanthoma;

lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;

bone;

colon, adenocarcinoma, adenoma;

pancreas, adenocarcinoma;

thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma;

seminoma;

melanoma;

sarcoma;

bladder carcinoma;

liver carcinoma and biliary passages;

kidney carcinoma;

myeloid disorders;

lymphoid disorders, Hodgkin's disease, hairy cells;

buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;

small intestine;

colon-rectum, large intestine, rectum;

brain and central nervous system; and

leukemia.

The compounds of the present invention can be administered to a patienteither alone; or a part of a pharmaceutical composition. Thecompositions can be administered to patients either orally, rectally,parenterally (intravenously, intramuscularly, or subcutaneously),intracisternally, intravaginally, intraperitoneally, intravesically,locally (powders, ointments, or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The term "pharmaceutically acceptable salts, esters, amides, andprodrugs" as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term "salts" refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the presentinvention. These salts can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Representative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium and amine cations including, butnot limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, S. M. Berge, et al., "PharmaceuticalSalts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein byreference.)

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁ -C₆ alkyl esters wherein thealkyl group is a straight or branched chain. Acceptable esters alsoinclude C₅ -C₇ cycloalkyl esters as well as arylalkyl esters such as,but not limited to benzyl. C₁ -C₄ alkyl esters are preferred. Esters ofthe compounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁ -C₆ alkyl amines and secondary C₁ -C₆ dialkyl amines wherein thealkyl groups are straight or branched chain. In the case of secondaryamines the amine may also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C₁ -C₃ alkyl primary amines, and C₁ -C₂ dialkyl secondary amines arepreferred. Amides of the compounds of the invention may be preparedaccording to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The compounds of the present invention can exist in differentstereoisomeric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisomeric forms of thecompounds, as well as mixtures thereof including racemic mixtures, formpart of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 1,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 100 mg per kilogram of bodyweight per day is preferable. The specific dosage used, however, canvary. For example, the dosage can depend on a numbers of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell known to those skilled in the art.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as throughmetabolism.

The examples presented below are intended to illustrate particularembodiments of the invention and are not intended to limit the scope ofthe specification, including the claims, in any way.

EXAMPLES

The compounds of Formula I can be prepared by the process described inScheme 1 below.

General Synthesis

The dimerisation of malononitrile in the presence of HBr gives2-bromo-3-cyano-4,6-diaminopyridine (II) as reported [W. J. Middleton,U.S. Patent, Chem. Abstracts, 1957;2,790,806(51):P14829;Carboni R. A.,Coffman D. D., Howard E. G., J. Am. Chem. Soc., 1958;80, 2838] but inslightly better yield (typically 79%-86% for a 0.5 mole scale reaction).Hydrogenolysis of this intermediate affords 3-cyano-4,6-diaminopyridine(III) [Metzger R., Oberdorfer J., Schwager C., Thielecke W., Boldt P.,Liebigs Ann. Chem., 1980;946-953] in good yield (typically 80%-91%).Subsequent hydrogenation of the cyanopyridine, for example in a mixtureof formic acid and water, employing Raney nickel catalyst provides thekey 4,6-diamino-3-pyridylcarboxaldehyde intermediate (IV) as previouslydescribed in U.S. Pat. No. 5,620,981, issued Apr. 15, 1997, which ishereby incorporated by reference. Depending on the grade of catalystused, it may be preferable to employ small, multiple additions of freshcatalyst over several days of reaction. The product can be isolated andpurified in good yield (typically 70%) by performing multipleextractions of the (filtered and neutralised) aqueous solution with anorganic solvent, for example ethyl acetate.

The aldehyde may then be condensed directly with an aryl acetonitrile toprovide a 3-aryl-2,7-diamino-1,6-naphthyridine (VI), also described inU.S. Pat. No. 5,620,981, after the manner reported by Hawes et al.[Hawes E. M., Gorecki D. K. J., J. Heterocycl. Chem., 1972;9,703]. Thisreaction is accomplished typically in a boiling alcohol (preferably2-ethoxyethanol) and in the presence of an alkoxide base (preferablysodium 2-ethoxyethoxide), which can be generated in situ by the additionof sodium metal or sodium hydride to the alcohol solvent. Although theuse of just over one equivalent of the aryl acetonitrile and a catalyticamount of base (preferably 0.4 equivalents) in a minimal amount ofsolvent is sufficient for complete reaction, better yields (74%-81%) maybe obtained with two equivalents of both the nitrile and the base. Thedesired product is separated by chromatography on a solid support(preferably silica gel) from reagent derived material and a minorby-product. This byproduct is a7-amino-2-(arylmethyl)pyrido[4,3d]pyrimidine (V), resulting from acondensation reaction involving the nitrile itself.

The 3-aryl-2,7-diamino-1,6-naphthyridine can be converted into a3-aryl-7-fluoro-1H-[1,6]naphthyridin-2-one; (VII) in reasonable yield(typically 50%-60%) by a diazotization reaction in 50% aqueous fluoboricacid, using a large excess (up to 8 equivalents) of solid sodium nitriteat low temperature (at or below -5° C.) for several days, after themanner previously described [Rewcastle G. W., Palmer B. D., Thompson A.M., Bridges A. J., Cody D. R., Zhou H., Fry D. J., McMichael A., DennyW. A. J. Med. Chem., 1996;39,1823]. The product from this reaction isobtained by extraction into an organic solvent (preferably ethylacetate), following careful low temperature neutralisation with aninorganic base (preferably sodium carbonate), then separation from thedione byproduct (VIII) by chromatography. This naphthyridin-2-oneintermediate may be N-alkylated in high yield by treatment with an alkyliodide in the presence of a base (preferably sodium hydride) in asuitable dry, unreactive solvent (preferably dimethylformamide) at 0 to20° C. A small amount of the product (X) from competing O-alkylation mayalso be obtained and can be removed by chromatography. The resultingl-alkyl-3-aryl-7-fluoro-1H-[1,6]naphthyridin-2-one (IX) is a versatile,reactive intermediate which can be reacted directly with eitheraliphatic amines in a suitable solvent (preferably 2-pentanol, or in thecase of gaseous amines in 2-propanol using a suitable pressure vessel)or with certain neat aryl amines at temperatures of 90 to 175° C. forbetween 30 minutes to 3 days to provide the compounds of Formula I whereR⁵ is an aryl group and the dotted line is a bond. Alternatively, thesame fluoro intermediate can be treated with the lithium anion of arylamines in a suitable dry, unreactive solvent (preferablytetrahydrofuran) at -78 to 20° C. for up to 3 days to give furthercompounds of Formula I. These compounds are typically purified bychromatography on silica gel and/or alumina and crystallisation fromsuitable solvents. ##STR20##

The compounds of Formula I can also be prepared by the process describedin Scheme 2below.

The key 4,6-diamino-3-pyridylcarboxaldehyde intermediate (IV) can bereacted with either a stabilized phosphorane, or a phosphonate ester inthe presence of a base, or any alternative Wittig or Horner-Emmonsreagent to provide the corresponding unsaturated ester. The resultingdouble bond can be trans, cis, or a mixture of both. For example,reaction of a 4,6-diamino-3-pyridylcarboxaldehyde with an excess amountof the stabilized phosphorane (carbethoxymethylene)triphenylphosphoranein 1,4-dioxane at reflux temperature gives mainly, or in some casesexclusively, the trans unsaturated ethyl ester (XI). Upon treatment withbase, ring closure occurs to give the desired7-amino-1,6-naphthyridin-2-one (XII). This reaction can be carried outusing a tertiary amine such as triethylamine or, preferably,N,N-diisopropylethylamine as the solvent, with 1 to 10 equivalents of1,8-diazabicyclo[5.4.0]undec-7-ene present. The reaction is carried outat elevated temperature, and is usually complete in 2 to 24 hours.Alternatively, the 4,6-diamino-3-pyridylcarboxaldehyde can be reactedwith a phosphonate ester such asbis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate using astrongly dissociated base (Tetrahedron Lett., 1983:4405) to givepredominately, if not exclusively, the cis unsaturated ester. Upontreatment with base under the conditions discussed previously, ringclosure occurs.

The naphthyridin-2-one intermediate (XII) may be N-alkylated in goodyield by treatment with an alkyl iodide in the presence of a base(preferably sodium hydride) in a suitable dry, unreactive solvent(preferably N,N-dimethylformamide) at 0 to 20° C. A small amount of theproduct (XIV) from competing O-alkylation may also be obtained and canbe removed by chromatography. The resulting1-alkyl-7-amino-1,6-naphthyridin-2-one (XIII) can be converted into a1-alkyl-7-fluoro-1,6-naphthyridin-2-one (XV) in reasonable yield(typically 50%-60%) by a diazotization reaction in 50% aqueous fluoboricacid, using an excess of solid sodium nitrite at low temperature (at orbelow -5° C.) for several hours. The product from this reaction isobtained by extraction into an organic solvent (preferably ethylacetate), following careful low temperature neutralisation with aninorganic base (preferably sodium carbonate), then purification bychromatography. The l-alkyl-7-fluoro-1,6-naphthyridin-2-one (XV) can bereacted directly with either aliphatic amines in a suitable solvent(preferably 2-pentanol, or in the case of gaseous amines in 2-propanolusing a suitable pressure vessel) or with certain neat aryl amines attemperatures of 90 to 175° C. for between 30 minutes to 3 days toprovide the compounds of Formula I where R⁵ is hydrogen and the dottedline is a bond. Alternatively, intermediate XV can be treated with thelithium anion of aryl amines in a suitable dry, non-reactive solvent(preferably tetrahydrofuran) at -78 to 20° C. for up to 3 days to givefurther compounds of Formula I. These compounds are typically purifiedby chromatography on silica gel and/or alumina and followed bycrystallization from suitable solvents. Compounds of Formula I can thenbe transformed to the dihydro congener of Formula I, where R5 ishydrogen and the dotted line is absent, by standard methods ofreduction. The preferred method is to use catalytic hydrogenation with astandard catalyst such as palladium on charcoal or Raney nickel. A rangeof solvents is possible for this transformation including loweralcohols, ethers, and lower alkyl amides. This transformation can alsobe carried out over a range of temperature and pressure. ##STR21##

Example A Preparation of7-amino-3-(2,6-dichlorophenyl)-1-methyl-1H-[1,6]naphthyridin-2-one

Trial 1

Anhydrous HBr (49 g, 0.60 mol) was added to a stirred mixture ofmalononitrile (37.5 g, 0.57 mol) and toluene (800 mL) at 0° C., then theresulting mixture was stirred at 20° C. for 16 hours, then at reflux for2hours. The resulting solution was cooled (to 0° C.), then the solid wascollected by filtration and oven dried. This material was then dissolvedin water (1 L) and the solution neutralised with 40% NaOH to give(crude) 2-bromo-3-cyano-4,6-diaminopyridine (II) (51.8 g, 86%): mp(water) 215.5-218.5° C. [W. J. Middleton, U.S. Patent, Chem. Abstracts,1957;2,790,806(51):P14829 records mp (EtOH) 255° C.; Carboni R. A.,Coffman D. D., Howard E. G., J. Am. Chem. Soc., 1958;80:2838 record mp260-265° C. dec.].

¹ H NMR [(CD₃)₂ SO] δ 6.66, 6.54 (2 br s, 2×2H, 2 NH₂), 5.60 (s, 1H,H-5).

¹³ C NMR δ 160.66, 157.46 (2 s, C-4,6), 143.73 (s, C-2), 117.00 (s, CN),86.37 (d, C-5), 85.31 (s, C-3).

Trial 2

Anhydrous HBr (90 g, 1.11 mol) was condensed into a Parr reactorcontaining 1,2-dichloroethane (500 mL) at 0° C. Malononitrile (40.0 g,0.605 mol) was added, the reactor sealed, and the resulting mixture wasshaken at 100° C. for 16 hours. The solution was cooled (to 0° C.), andthe solid was collected by filtration, then suspended in water (150 mL).The aqueous suspension was adjusted to pH 9 with concentrated aqueousammonia hydroxide, stirred for 2 hours, then filtered. The collectedsolid was washed well with water, and dried to give2-bromo-3-cyano-4,6-diaminopyridine (II) (42.4 g, 66%): mp (water)215.5-218.5° C. [W. J. Middleton, U.S. Patent, Chem. Abstracts,1957;2,790,806(51):P14829 records mp (EtOH) 255° C.; Carboni R. A.,Coffman D. D., Howard E. G., J. Am. Chem. Soc., 1958;80:2838 record mp260-265° C. dec.]. The spectral data were the same as observed in Trial1.

A solution of (II) (15.1 g, 0.071 mol), KOAc (7.0 g, 0.071 mol) and 5%Pd/C (4 g) in THF (tetrahydrofuran) (130 mL) and MeOH (methanol) (70 mL)was hydrogenated (55 psi/20° C.) for 7 days. The resulting solution wasfiltered over Celite, washing with THF/MeOH, then the solvents wereremoved under reduced pressure. The residue was dissolved in dilute HCl,then the solution neutralised with 40% NaOH and excess Na₂ CO₃ to give3-cyano-4,6-diaminopyridine (III) (6.58 g, 69%): mp (water) 197-198° C.[Metzger R., Oberdorfer J., Schwager C., Thielecke W., Boldt P., LiebigsAnn. Chem., 1980;946-953 record mp (benzene) 205° C.].

¹ H NMR [(CD₃)₂ SO] δ 7.91 (s, 1H, H-2), 6.26, 6.24 (2 br s, 2×2H,2NH₂), 5.63 (s, 1H, H-5).

¹³ C NMR δ 161.98, 155.48 (2 s, C-4,6), 153.86 (d, C-2), 118.10 (s, CN),87.71 (d, C-5), 83.34 (s, C-3). Extraction of the remaining liquor withEtOAc (4×200 mL) gave additional (III) (2.12 g, 22%).

A solution of (III) (5.00 g, 37.3 mmol) and freshly prepared W-7 Raneynickel (120 mg wet catalyst, in absolute EtOH [ethanol]) in 99% formicacid (150 mL) and water (40 mL) was hydrogenated (60 psi/20° C.) for 2days. Fresh catalyst was added (130 mg) and the reaction continued for 5days, then further catalyst added (207 mg) and the reaction continuedfor 2 days. The resulting solution was filtered over Celite, washingwith formic acid, then the solvents were removed under reduced pressure.The residue was diluted with water (150 mL), then excess Na₂ CO₃ wasadded, and the solution extracted with EtOAc (ethyl acetate) (15×100mL). Removal of the solvent gave a solid (3.65 g, 71%) which was useddirectly. Chromatography of a sample on neutral alumina, eluting with1-3% MeOH/CHCl₃, gave 4,6-diamino-3-pyridylcarboxaldehyde (IV): mp(MeOH/CHCl₃ /light petroleum) 343° C.

¹ H NMR [(CD₃)₂ SO] δ 9.48 (s, 1H, CHO), 8.04 (s, 1H, H-2), 7.12, 6.46(2 br s, 2×2H, 2NH₂), 5.55 (s, 1H, H-5).

¹³ C NMR δ 190.27 (d, CHO), 162.34 (s, C-4 or 6), 159.77 (d, C-2),155.14 (s, C-4 or 6), 110.45 (s, C-3), 86.98 (d, C-5).

Analysis calculated for C₆ H₇ N₃ OHCl requires:

C, 41.5; H, 4.7; N, 24.2%.

Found: C, 41.5; H, 4.6; N, 24.1%.

To a solution of sodium (31.5 mg, 1.37 mmol) dissolved in2-ethoxyethanol (1.3 mL) was added 2,6-dichlorophenylacetonitrile (0.70g, 3.76 mmol) and (IV) (467 mg, 3.41 mmol), and the mixture was thenstirred at reflux for 2 hours. The solvent was removed under reducedpressure, then the residue was diluted with aqueous NaHCO₃ (50 mL) andextracted with EtOAc (5×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 0-0.5%MeOH/CHCl₃, gave firstly7-amino-2-[(2,6-dichlorophenyl)methyl]pyrido-[4,3-d]pyrimidine (V) (61mg, 6%): mp (MeOH/CHCl₃ /light petroleum) 205-206° C.

¹ H NMR [(CD₃)₂ SO] δ 9.12, 8.93 (2 s, 2H, H-4,5), 7.50 (d, J=8.1 Hz, 2HH-3',5'), 7.35 (dd, J=8.5, 7.7 Hz, 1H, H-4'), 6.91 (br s, 2H, NH₂), 6.36(s, 1H, H-8), 4.55 (s, 2H, CH₂).

¹³ C NMR δ 166.88 (s, C-2), 162.45 (s, C-7), 160.45 (d, C-4), 154.27 (d,C-5), 153.96 (s, C-8a), 135.64 (s, 2C, C-2',6'), 134.12 (s, C-1'),129.23 (d, C-4'), 128.22 (d, 2 C, C-3',5'), 112.88 (s, C-4a), 95.01 (d,C-8), 40.86 (t, CH₂).

Analysis calculated for C₁₄ H₁₀ Cl₂ N₄ requires:

C, 55.1; H, 3.3; N, 18.4%.

Found: C, 55.2; H, 3.0; N, 18.6%.

Further elution with 0.5-3% MeOH/CHCl₃ gave2,7-diamino-3-(2,6-dichlorophenyl)-[1,6]naphthyridine (VI) (708 mg,68%): mp (CH₂ Cl₂ /light petroleum) 218-219° C.

¹ H NMR [(CD₃)₂ SO] δ 8.40 (s, 1H, H-5), 7.59 (d, J=7.8 Hz, 2H, H-3'5'),7.59 (s, 1H, H-4), 7.46 (dd, J=8.7, 7.4 Hz, 1H, H-4'), 6.29 (s, 1H,H-8), 6.26, 5.94 (2 br s, 2×2H, 2NH₂).

¹³ C NMR δ 159.84, 157.68 (2 s, C-2,7), 153.27 (s, C-8a), 150.40 (d,C-5), 136.91 (d, C-4), 135.26 (s, 2 C, C-2',6'), 134.52 (s, C-1'),130.61 (d, C-4'), 128.48 (d, 2 C, C-3',5'), 116.30, 112.72 (2 s,C-3,4a), 95.43 (d, C-8).

Analysis calculated for C₁₄ H₁₀ Cl₂ N₄ requires:

C, 55.1; H, 3.3; N, 18.4%.

Found: C, 55.3; H, 3.5;N, 18.0%.

Alternative Conditions. To a solution of sodium (169 mg, 7.35 mmol)dissolved in 2-ethoxyethanol (7.0 mL) was added2,6-dichlorophenylacetonitrile (1.40 g, 7.53 mmol) and (IV) (502 mg,3.66 mmol), and the mixture was then stirred at reflux for 30 minutes.The resulting solution was diluted with aqueous NaHCO₃ (50 mL) andextracted with EtOAc (3×50 mL). The solvents were removed under reducedpressure, then chromatography of the residue on silica gel, eluting with2-3% MeOH/CH₂ Cl₂, gave firstly a mixed fraction, which oncrystallisation from CHCl₃ /light petroleum gave2,6-dichlorophenylacetamide (165 mg): mp (MeOH/CH₂ Cl₂) 211.5-213° C.

¹ H NMR [(CD₃)₂ SO] δ 7.53 (br s, 1H, NH), 7.44 (d, J=8.1 Hz, 2H,H-3,5), 7.30 (dd, J=8.5, 7.6 Hz, 1H, H-4), 7.02 (br s, 1H, NH), 3.77 (s,2H, CH₂).

¹³ C NMR δ 169.60 (s, CONH₂), 135.56 (s, 2 C, C-2,6), 132.67 (s, C-1),129.22 (d, C-4), 128.09 (d, 2 C, C-3,5), 37.31 (t, CH₂).

Analysis calculated for C₈ H₇ Cl₂ NO) requires:

C, 47.1; H, 3.4; N, 6.9%

Found: C, 47.3; H, 3.5; N, 7.1%.

Further crystallisation of the liquors gave (V) (42 mg, 4%). Furtherelution of the column with 4-4.5% MeOH/CH₂ Cl₂ gave (VI) (920 mg, 82%).

A suspension of (VI) (1.55 g, 5.08 mmol) in 50% HBF₄ (75 mL) at -5° C.was treated with solid NaNO₂ (3.0 g, 43.5 mmol, added in small portionsover 5 hours), then kept at -20° C. for 5 days. The resulting mixturewas neutralised with solid Na₂ CO₃ /ice, keeping the temperature below-10° C., and extracted with EtOAc (4×150 mL). The solvent was removed,then chromatography of the residue on silica gel, eluting with 1-2%MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-7-fluoro-1H-[1,6]naphthyridin-2-one; (VII) (0.91g, 58%): mp (CH₂ Cl₂ /light petroleum) 254.5-255.5° C.

¹ H NMR [(CD₃)₂ SO] δ 12.54 (br s, 1H, NH), 8.66 (s, 1H, H-5), 8.13 (s,1H, H-4), 7.61 (d, J=8.2 Hz, 2H, H-3',5'), 7.49 (dd, J=8.8, 7.4 Hz, 1H,H-4'), 6.89 (s, 1H, H-8).

¹³ C NMR δ 163.55 (d, J_(C-F) =234 Hz, C-7), 159.77 (s, C-2), 148.95(dd, J_(C-F) =19 Hz, C-5), 147.69 (d, J_(C-F) =12 Hz, C-8a), 138.13 (d,C-4), 134.51 (s, 2 C C-2',6'), 133.51 (s, C-1'), 130.85 (d, C4'), 129.61(d, J_(C-F) =2.5 Hz, C-3), 128.08 (d, 2 C, C-3',5'), 114.34 (d, J_(C-F)=2.5 Hz, C-4a), 92.95 (dd, J_(C-F) =42 Hz, C-8).

Analysis calculated for C₁₄ H₇ Cl₂ FN₂ O requires:

C, 54.4; H, 2.3; N, 9.1; F, 6.2%.

Found: C, 54.0; H, 2.0; N, 9.2; F, 6.1%.

Further elution with 10-12% MeOH/CH₂ Cl₂ gave3-(2,6-dichlorophenyl)-1H,6H-[1,6]naphthyridine-2,7-dione; (VIII) (0.45g, 29%): mp (MeOH/CHCl₃) 363-369° C. dec.

¹ H NMR [(CD₃)₂ SO] δ 12.07, 11.55 (2 br s, 2H, 2NH), 8.10 (s, 1H, H-5),7.67 (s, 1H, H-4), 7.56 (d, J=8.1 Hz, 2H, H-3',5'), 7.44 (dd, J=8.8,7.5Hz, 1H, H-4'), 5.90 (s, 1H, H-8).

¹³ C NMR δ 161.84, 160.38 (2 s, C-2,7), 147.87 (s, C-8a), 139.65 (br d,C-5), 138.60 (d, C-4), 134.90 (s, 2 C, C-2',6'), 133.90 (s, C-1'),130.50 (d, C4'), 127.97 (d, 2 C, C-3',5'), 124.18 (s, C-3), 105.09 (s,C-4a), 95.50 (d, C-8).

Analysis calculated for C₁₄ H₈ Cl₂ N₂ O₂ requires:

C, 54.7; H, 2.6; N, 9.1%.

Found: C, 54.6; H, 2.5; N, 9.0%.

To a stirred solution of (VII) (2.00 g, 6.47 mmol) in dry DMF (50 mL) at0° C. was added 60% NaH (0.31 g, 7.75 mmol), followed by Mel (0.48 mL,8.03 mmol) and the mixture stirred at 0° C. for 2 hours. The solvent wasremoved under reduced pressure, then the residue was diluted withaqueous NaHCO₃ (100 mL) and extracted with EtOAc (3×150 mL). The solventwas removed, then chromatography of the residue on silica gel, elutingwith 33% light petroleum/CH₂ Cl₂, gave firstly3-(2,6-dichlorophenyl)-7-fluoro-2-methoxy-[1,6]naphthyridine (X, whereR² is methyl) (39 mg, 2%): mp (CH₂ Cl₂ /light petroleum) 165-165.5° C.

¹ H NMR [(CD₃)₂ SO] δ 9.05 (s, 1H, H-5), 8.51 (s, 1H, H-4), 7.66 (d,J=8.2 Hz, 2H, H-3',5'), 7.53 (dd, J=8.6, 7.6 Hz, 1H, H-4'), 7.49 (s, 1H,H-8), 4.02 (s, 3H, OCH₃).

¹³ C NMR δ 163.68 (d, J_(C-F) =234 Hz, C-7), 162.59 (s, C-2), 152.93 (d,J_(C-F) =13 Hz, C-8a), 150.80 (dd, J_(C-F) =18 Hz, C-5), 139.53 (d,C-4), 134.33 (s, 2 C, C-2',6'), 133.02 (s, C-1), 131.11 (d, C-4'),128.27 (d, 2 C, C-3',5'), 122.19 (d, J_(C-F) =2.4 Hz, C-3), 119.46 (d,J_(C-F) =3.0 Hz, C-4a), 102.52 (dd, J_(C-F) =37 Hz, C-8), 54.58 (q,OCH₃).

Analysis calculated for C₁₅ H₉ Cl₂ FN₂ O requires:

C, 55.8; H, 2.8; N, 8.7%.

Found: C, 55.8; H, 3.0; N, 8.5%.

Further elution with CH₂ Cl₂ gave3-(2,6-dichlorophenyl)-7-fluoro-1-methyl-1H-[1,6]naphthyridin-2-one;(IX; where R² is methyl) (1.88 g, 90%): mp (CH₂ Cl₂ /light petroleum)201-203° C.

¹ H NMR [(CD₃)₂ SO] δ 8.70 (s, 1H, H-5), 8.16 (s, 1H, H-4), 7.61 (d,J=8.0 Hz, 2H, H-3',5'), 7.50 (dd, J=8.7, 7.3 Hz, 1H, H-4'), 7.38 (s, 1H,H-8), 3.66 NCH₃).

¹³ C NMR δ 164.21 (d, J_(C-F) =234 Hz, C-7), 159.23 (s, C-2), 149.16(dd, J_(C-F) =19 Hz, C-5), 148.57 (d, J_(C-F) =12 Hz, C-8a), 137.48 (d,C-4), 134.47 (s, 2 C, C-2',6'), 133.85 (s, C-1), 130.88 (d, C-4'),128.51 (d, J_(C-F) =2.7 Hz, C-3), 128.11 (d, 2 C, C-3',5'), 114.64 (d,J_(C-F) =3.0 Hz, C-4a), 93.91 (dd, J_(C-F) =43 Hz, C-8), 29.90 (q,NCH₃).

Analysis calculated for C₁₅ H₉ Cl₂ FN₂ O requires:

C, 55.8; H, 2.8; N, 8.7; F, 5.9%.

Found: C, 55.8; H, 2.5; N, 8.5; F, 5.9%.

A solution of (IX, where R² is methyl) (80 mg, 0.25 mmol) and 25%ammonium hydroxide (5.0 mL, 66 mmol) in 2-propanol (30 mL) was saturatedwith ammonia (gas) and stirred at 170° C. in a pressure vessel for 3days. The solvent was removed, then the residue was diluted with aqueousNa₂ CO₃ (50 mL) and extracted with CH₂ Cl₂ (3×50 mL). The solvent wasremoved, then chromatography of the residue on silica gel, eluting with1-2% MeOH/CH₂ Cl₂, gave7-amino-3-(2,6-dichlorophenyl)-1-methyl-1H-[1,6]naphthyridin-2-one; (70mg, 88%): mp 239-240° C.

¹ H NMR [(CD₃)₂ SO] δ 8.37 (s, 1H, H-5), 7.76 (s, 1H, H-4), 7.56 (d,J=8.2 Hz, 2H, H-3',5'), 7.43 (dd, J=8.7, 7.4 Hz, 1H, H-4'), 6.65 (br s,2H, NH₂), 6.30 (s, 1H, H-8), 3.49 (s, 3H, NCH₃).

¹³ C NMR δ 161.24, 159.76 (2 s, C-2,7), 150.91 (d, C-5), 146.26 (s,C-8a), 138.32 (d, C-4), 135.07 (s, 2C, C-2',6'), 135.03 (s, C-1'),130.23 (d, C-4'), 127.96 (d, 2 C, C-3',5'), 122.19 (s, C-3), 108.18 (s,C-4a), 88.28 (d, C-8), 28.76 (q, NCH₃).

Analysis calculated for C₁₅ H₁₁ Cl₂ N₃ O requires:

C, 56.3; H, 3.5; N, 13.1%.

Found:C, 56.1; H, 3.3; N, 13.1%.

Example B Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (103 mg, 0.32 mmol) and 40%aqueous methylamine (5.0 mL, 58 mmol) in 2-propanol (30 mL) was stirredat 100° C. in a pressure vessel for 5 hours. The solvent was removed,then the residue was diluted with aqueous Na₂ CO₃ (50 mL) and extractedwith CH₂ Cl₂ (3×50 mL). Removal of the solvent gave3-(2,6-dichlorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one;(103 mg, 97%): mp (CH₂ Cl₂ /light petroleum) 252-253.5° C.

¹ H NMR [(CD₃)₂ SO] δ 8.42 (s, 1H, H-5), 7.76 (s, 1H, H-4), 7.56 (d,J=8.0 Hz, 2H, H-3',5'), 7.43 (dd, J=8.7, 7.3 Hz, 1H, H-4'), 7.15 (br q,J=4.8 Hz, 1H, NHCH₃), 6.20 (s, 1H, H-8), 3.53 (s, 3H, NCH₃), 2.88 (d,J=4.9 Hz, 3H, NHCH₃).

¹³ C NMR δ 160.76, 159.77 (2 s, C-2,7),150.71 (d, C-5), 146.15 (s,C-8a), 138.32 (d, C-4), 135.05 (s, 2 C, C-2',6'), 135.04 (s, C-1'),130.19 (d, C-4'), 127.93 (d, 2C, C-3',5'), 122.03 (s, C-3), 108.03 (s,C-4a), 86.98 (br d, C-8), 28.82, 28.23 (2NCH₃).

Analysis calculated for C₁₆ H₁₃ Cl₂ N₃ O requires:

C, 57.5; H, 3.9; N, 12.6%.

Found: C, 57.5; H, 4.0; N, 12.6%.

Example C Preparation of3-(2,6-dichlorophenyl)-7-dimethylamino-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (102 mg, 0.32 mmol) and 40%aqueous dimethylamine (5.0 mL, 40 mmol) in 2-propanol (50 mL) wasstirred at 90° C. in a pressure vessel for 30 minutes. The solvent wasremoved, then the residue was diluted with aqueous Na₂ CO₃ (50 mL) andextracted with EtOAc (4×50 mL). Removal of the solvent gave3-(2,6-dichlorophenyl)-7-dimethylamino-1-methyl-1H-[1,6]naphthyridin-2-one;(107 mg, 97%): mp (CH₂ Cl₂ /light petroleum) 265-266° C.

¹ H NMR (CDCl₃) δ 8.40 (s, 1H, H-5), 7.54 (s, 1H, H-4), 7.39 (d, J=8.2Hz, 2H, H-3',5'), 7.24 (dd, J=8.6, 7.7 Hz, 1H, H-4'), 6.09 (s, 1H, H-8),3.67 (s, 3H, NCH₃), 3.22 (s, 6H, N(CH₃)₂).

¹³ C NMR δ 160.90, 160.02 (2 s, C-2,7), 150.15 (d, C-5), 146.95 (s,C-8a), 138.29 (d, C-4), 135.88 (s, 2C, C-2',6'), 135.01 (s, C-1'),129.48 (d, C-4'), 127.91 (d, 2 C, C-3',5'), 123.80 (s, C-3), 108.33 (s,C-4a), 86.64 (d, C-8), 38.40 (q, 2 C, N(CH₃)₂), 29.27 (q, NCH₃).

Analysis calculated for C₁₇ H₁₅ Cl₂ N₃ O requires:

C, 58.6; H, 4.3; N, 12.1%.

Found: C, 58.9; H, 4.2; N, 12.4%.

Example D Preparation of3-(2,6-dichlorophenyl)-7-[2-(diethylamino)ethylamino]-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (101 mg, 0.31 mmol) andN,N-diethylethylenediamine (0.45 mL, 3.21 mmol) in 2-pentanol (10 mL)was stirred at 115° C. for 15 hours. The solvent was removed underreduced pressure, then the residue was diluted with aqueous Na₂ CO₃ (50mL) and extracted with EtOAc (3×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 2% MeOH/CH₂Cl₂ containing 0.3% Et₃ N, gave a crude product, which was treated withaqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL). The solvent wasremoved, then chromatography of the residue on alumina, eluting with0.25-0.3% MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-7-[2-(diethylamino)ethylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;(81 mg, 62%): mp (hexane/Et₂ O) 100-102° C.

¹ H NMR (CDCl₃) δ 8.34 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.39 (d, J=8.1Hz, 2H, H-3',5'), 7.24 (dd, J=8.5, 7.7 Hz, 1H, H-4'), 6.07 (s, 1H, H-8),5.67 (br s, 1H, NH), 3.65 (s, 3H, NCH₃), 3.38 (q, J=5.6 Hz, 2H, NHCH₂),2.75 (t, J=6.0 Hz, 2H, NCH₂), 2.60 (q, J=7.1 Hz, 4H, N(CH₂)₂), 1.06 (t,J=7.1 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.80, 159.93 (2 s, C-2,7), 150.77 (d, C-5), 147.16 (s,C-8a), 138.31 (d, C-4), 135.86 (s, 2C, C-2',6'), 134.91 (s, C-1'),129.51 (d, C4'), 127.92 (d, 2 C, C-3',5'), 123.98 (s, C-3), 109.27 (s,C-4a), 87.23 (d, C-8), 51.16 (t, NCH₂), 46.53 (t, 2 C, N(CH₂)₂), 39.76(t, NCH₂), 29.37 (q, NCH₃), 11.69 (q, 2 C, 2CH₃).

Analysis calculated for C₂₁ H₂₄ Cl₂ N₄ O requires:

C, 60.2; H, 5.8; N, 13.4%.

Found: C, 60.1; H, 5.6; N, 13.2%.

Example E Preparation of3-(2,6-dichlorophenyl)-7-[3-(diethylamino)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (101 mg, 0.31 mmol) and3-(diethylamino)propylamine (0.50 mL, 3.18mmol) in 2-pentanol (10 mL)was stirred at reflux for 17 hours. The solvent was removed underreduced pressure, then the residue was diluted with aqueous Na₂ CO₃ (50mL) and extracted with EtOAc (4×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 2-4% MeOH/CH₂Cl₂ containing 0.3% Et₃ N, gave a crude product, which was treated withaqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (3×50mL) to give3-(2,6-dichlorophenyl)-7-[3-(diethylamino)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;(127 mg, 94%): mp (CH₂ Cl₂ /light petroleum) 118-120° C.

¹ H NMR (CDCl₃) δ 8.33 (s, 1H, H-5), 7.51 (s, 1H, H-4), 7.39 (d, J=8.3Hz 2H z, H-3',5'), 7.24 (dd, J=8.6, 7.7 Hz, 1H, H-4'), 6.36 (br s, 1H,NH), 6.01 (s, 1H, H-8), 3.64 (s, 3H, NCH₃), 3.43 (td, J=6.1, 5.3 Hz, 2H,NHCH₂), 2.60 (t, J=6.3 Hz, 2H, NCH₂), 2.57 (q, J=7.1 Hz, 4H,N(CH₂)₂),1.83 (pentet, J=6.3 Hz, 2H, CH₂), 1.07 (t, J=7.1 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.82, 160.05 (2 s, C-2,7), 150.87 (d, C-5), 147.14 (s,C-8a), 138.36 (d, C-4), 135.88 (s, 2 C, C-2',6'), 134.96 (s, C-1'),129.48 (d, C-4'), 127.91 (d, 2 C, C-3',5'), 123.72 (s, C-3), 109.11 (s,C-4a), 86.65 (d, C-8), 51.87 (t, NCH₂), 47.01 (t, 2 C, N(CH₂)₂), 42.34(t, NCH₂), 29.32 (q, NCH₃), 25.95 (t, CH₂), 11.81 (q, 2 C, 2 CH₃).

Analysis calculated for C₂₂ H₂₆ Cl₂ N₄ O requires:

C, 61.0; H, 6.1; N, 12.9%.

Found: C, 61.0; H, 5.9; N, 12.8%.

Example F Preparation of3-(2,6-dichlorophenyl)-7-[4-(diethylamino)butylamino]-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (104 mg, 0.32 mmol) and4-(diethylamino)butylamine (0.51 g, 3.54 mmnol) in 2-pentanol (10 mL)was stirred at reflux for 1 day. The solvent was removed under reducedpressure, then the residue was diluted with aqueous Na₂ CO₃ (50 mL) andextracted with EtOAc (3×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 2-5% MeOH/CH₂Cl₂ containing 0.3% Et₃ N, gave a crude product, which was treated withaqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL). The solvent wasremoved, then chromatography of the residue on alumina, eluting with0.5-1% MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-7-[4-(diethylamino)butylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;(125 mg, 87%): mp (pentane) 123-124.5° C.

¹ H NMR (CDCl₃) δ 8.32 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.39 (d, J=8.4Hz, 2H, H-3',5'), 7.24 (dd, J=8.5, 7.6 Hz, 1H, H-4'), 6.03 (s, 1H, H-8),5.59 (br s, 1H, NH), 3.64 (s, 3H, NCH₃), 3.35 (td, J=6.5, 4.6 Hz, 2H,NHCH₂), 2.56 (q, J=7.2 Hz, 4H, N(CH₂)₂), 2.49 (t, J=7.1 Hz, 2H, NCH₂),1.74 (pentet, J=7.0 Hz, 2H, CH₂), 1.62 (pentet, J=7.0 Hz, 2H, CH₂), 1.05(t, J=7.1 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.81, 159.92 (2 s, C-2,7), 150.80 (d, C-5), 147.17 (s,C-8a), 138.32 (d, C-4), 135.86 (s, 2 C, C-2',6'), 134.92 (s, C-1'),129.51 (d, C-4'), 127.91 (d, 2 C, C-3',5'), 123.89 (s, C-3), 109.21 (s,C-4a), 86.72 (d, C-8), 52.57 (t, NCH₂), 46.69 (t, 2 C, N(CH₂)₂), 42.47(t, NCH₂), 29.34 (q, NCH₃), 27.37, 24.91 (2 t, 2CH₂), 11.47 (q, 2 C,2CH₃).

Analysis calculated for C₂₃ H₂₈ Cl₂ N₄ O requires:

C, 61.8; H, 6.3; N, 12.5%.

Found: C, 61.6; H, 6.5; N, 12.4%.

Example G Preparation of3-(2,6-dichlorophenyl)-7-[5-(diethylamino)pentylamino]-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (94 mg, 0.29 mmol) and5-(diethylamino)pentylamine (0.52 g of ca 90%, 2.96 mmol) in 2-pentanol(10 mL) was stirred at reflux for 18 hours. The solvent was removedunder reduced pressure, then the residue was diluted with aqueous Na₂CO₃ (50 mL) and extracted with EtOAc (4×50 mL). The solvent was removed,then chromatography of the residue on silica gel, eluting with 1-2%MeOH/CH₂ Cl₂ containing 0.3% Et₃ N, gave a crude product, which wastreated with aqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL). Thesolvent was removed, then chromatography of the residue on alumina,eluting with 1% EtOH/CHCl₃, gave3-(2,6-dichlorophenyl)-7-[5-(diethylamino)pentylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;(125 mg, 93%): foam.

¹ H NMR (CDCl₃) δ 8.32 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.40 (d, J=8.0Hz, 2H, H-3',5'), 7.24 (dd, J=8.6, 7.7 Hz, 1H, H-4'), 6.04 (s, 1H, H-8),5.06 (br t, J=5.4 Hz, 1H, NHCH₂), 3.65 (s, 3H, NCH₃), 3.34 (td, J=6.9,5.7 Hz, 2H, NHCH₂), 2.53 (q, J=7.2 Hz, 4H, N(CH₂)₂), 2.44 (t, J=7.4 Hz,2H, NCH₂), 1.73 (pentet, J=7.2 Hz, 2H, CH₂), 1.54, 1.46 (2 pentet, J=7.5Hz, 2×2H, 2CH₂), 1.03 (t, J=7.2 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.78, 159.86 (2 s, C-2,7), 150.76 (d, C-5), 147.25 (s,C-8a), 138.28 (d, C-4), 135.85 (s, 2 C, C-2',6'), 134.87 (s, C-1'),129.53 (d, C4'), 127.92 (d, 2 C, C-3',5'), 124.05 (s, C-3), 109.30 (s,C-4a), 86.61 (d, C-8), 52.73 (t, NCH₂), 46.86 (t, 2 C, N(CH₂)₂), 42.47(t, NCH₂), 29.38 (q, NCH₃), 29.15, 26.85, 25.07 (3 t, 3CH₂), 11.59 (q, 2C, 2CH₃).

Analysis calculated for C₂₄ H₃₀ Cl₂ N₄ O requires:

C, 62,5; H, 6.6; N, 12.1%.

Found: C, 62.2; H, 6,7; N, 11.8%.

Example H Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (80 mg, 0.25 mmol) and1-(3-aminopropyl)4-methylpiperazine (0.42 g, 2.66 mmol) in 2-pentanol(10 mL) was stirred at reflux for 16 hours. The solvent was removedunder reduced pressure, then the residue was diluted with aqueous Na₂CO₃ (50 mL) and extracted with EtOAc (3×50 mL). The solvent was removed,then chromatography of the residue on silica gel, eluting with 3-6%MeOH/CH₂ Cl₂ containing 0.3% Et₃ N, gave a crude product, which wastreated with aqueous Na₂ CO₃ and extracted with EtOAc (3×50 mL) to give3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;(99 mg, 87%):

mp (CH₂ Cl ₂ /hexane) 164-166° C.

¹ H NMR [(CD₃)₂ SO] δ 8.40 (s, 1H, H-5), 7.74 (s, 1H, H-4), 7.56 (d,J=7.9 Hz, 2H, H-3',5'), 7.43 (dd, J=8.7, 7.5 Hz, 1H, H4'), 7.21 (br t,J=5.6 Hz, 1H, NHCH₂), 6.24 (s, 1H, H-8), 3.50 (s, 3H, NCH₃), 3.34 (q,J=6.4 Hz, 2H, NHCH₂), 2.6-2.1 (br s, 8H, N(CH₂)₄ N), 2.36 (t, J=7.1 Hz,2H, NCH₂), 2.14 (s, 3H, NCH₃), 1.71 (pentet, J=6.9 Hz, 2H, CH₂).

¹³ C NMR δ 160.15, 159.80 (2 s, C-2,7), 150.73 (d, C-5), 146.07 (s,C-8a), 138.32 (d, C-4), 135.07 (s, 3C, C-1',2',6'), 130.23 (d, C4'),127.97 (d, 2 C, C-3',5'), 122.04 (s, C-3), 108.10 (s, C-4a), 87.73 (brd, C-8), 55.53 (t, NCH₂), 54.70, 52.66 (2 t, 2×2 C, N(CH₂)₄ N), 45.67(q, NCH₃), 39.43 (t, NCH₂), 28.81 (q, NCH₃), 26.07 (t, CH₂).

Analysis calculated for C₂₃ H₂₇ Cl₂ N₅ O requires:

C, 60.0; H, 5.9; N, 15.2%.

Found: C, 59.8; H, 6.2; N, 15.0%.

Example I Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-methylpiperazin-1-yl)butylamino]-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (101 mg, 0.31 mmol) and1-(4-aminobutyl)-4-methylpiperazine (0.55 g, 3.22 mmol) in 2-pentanol(10 mL) was stirred at reflux for 16 hours. The solvent was removedunder reduced pressure, then the residue was diluted with aqueous Na₂CO₃ (50 mL) and extracted with EtOAc (3×50 mL). The solvent was removed,then chromatography of the residue on silica gel, eluting with 24%MeOH/CH₂ Cl₂ containing 0.3% Et₃ N, gave a crude product, which wastreated with aqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL). Thesolvent was removed, then chromatography of the residue on alumina,eluting with 1% EtOH/CHCl₃, gave3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-methylpiperazin-1-yl)butylamino]-1H-[1,6]naphthyridin-2-one;(140 mg, 94%): foam.

¹ H NMR (CDCl₃) δ 8.32 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.39 (d, J=8.1Hz, 2H, H-3',5'), 7.23 (dd, J=8.6, 7.7 Hz, 1H, H-4'), 6.03 (s, 1H, H-8),5.54 (br s, 1H, NHCH₂), 3.64 (s, 3H, NCH₃), 3.36 (td, J=6.2, 4.4 Hz, 2H,NHCH₂), 2.8-2.2 (br s, 8H, N(CH₂)₄ N), 2.42 (t, J=7.1 Hz, 2H, NCH₂),2.30 (s, 3H, NCH₃), 1.75 (pentet, J=6.7 Hz, 2H, CH₂), 1.66 (pentet,J=6.9 Hz, 2H, CH₂).

¹³ C NMR δ 160.75, 159.85 (2 s, C-2,7), 150.74 (d, C-5), 147.13 (s,C-8a), 138.27 (d, C-4), 135.81 (s, 2 C, C-2',6'), 134.85 (s, C-1'),129.49 (d, C-4'), 127.88 (d, 2 C, C-3',5'), 123.88 (s, C-3), 109.19 (s,C-4a), 86.67 (d, C-8), 57.90 (t, NCH₂), 55.02, 53.11 (2 t, 2×2 C,N(CH₂)₄ N), 46.00 (q, NCH₃), 42.35 (t, NCH₂), 29.34 (q, NCH₃), 27.08,24.47 (2 t, 2CH₂).

Analysis calculated for C₂₄ H₂₉ Cl₂ N₅ O.0.5 H₂ O requires:

C, 59.6; H, 6.3; N, 14.5%.

Found: C, 59.6; H, 5.9; N, 14.5%.

Example J Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[5-(4-methylpiperazin-1-yl)pentylamino]-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (102 mg, 0.32 mmol) and1-(5-aminopentyl)-4-methylpiperazine (0.56 g, 3.03 mmol) in 2-pentanol(10 mL) was stirred at reflux for 1 day. The solvent was removed underreduced pressure, then the residue was diluted with aqueous Na₂ CO₃ (50mL) and extracted with EtOAc (4×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 2-4% MeOH/CH₂Cl₂ containing 0.3% Et₃ N, gave a crude product, which was treated withaqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL). The solvent wasremoved, then chromatography of the residue on alumina, eluting with0.25-0.5% MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-1-methyl-7-[5-(4-methylpiperazin-1-yl)pentylamino]-1H-[1,6]naphthyridin-2-one;(109 mg, 71%): foam.

¹ H NMR (CDCl₃) δ 8.32 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.40 (d, J=8.0Hz, 2H, H-3',5'), 7.24 (dd, J=8.6, 7.8 Hz, 1H, H-4'), 6.03 (s, 1H, H-8),5.01 (br t, J=5.4 Hz, 1H, NHCH₂), 3.65 (s, 3H, NCH₃), 3.34 (td, J=6.9,5.8 Hz, 2H, NHCH₂), 2.8-2.1 (br s, 8H, N(CH₂)₄ N), 2.37 (t, J=7.6 Hz,2H, NCH₂), 2.29 (s, 3H, NCH₃), 1.73 (pentet, J=7.3 Hz, 2H, CH₂), 1.58(pentet, J=7.5 Hz, 2H, CH₂), 1.47 (pentet, J=7.4 Hz, 2H, CH₂).

¹³ C NMR δ 160.78, 159.84 (2 s, C-2,7), 150.77 (d, C-5), 147.26 (s,C-8a), 138.27 (d, C-4), 135.85 (s, 2 C, C-2',6'), 134.86 (s, C-1'),129.55 (d, C-4'), 127.93 (d, 2 C, C-3',5'), 124.10 (s, C-3), 109.33 (s,C-4a), 86.62 (d, C-8), 58.45 (t, NCH₂), 55.11, 53.26 (2 t, 2×2 C,N(CH₂)₄ N), 46.04 (q, NCH₃), 42.43 (t, NCH₂), 29.40 (q, NCH₃), 29.11,26.60, 24.98 (3 t, 3CH₂).

Analysis calculated for C₂₅ H₃₁ Cl₂ N₅ O.0.75 H₂ O requires:

C, 59.8; H, 6.5; N, 14.0%.

Found: C, 59.7; H, 6.5; N, 13.8%.

Example K Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-morpholino)propylamino]-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (103 mg, 0.32 mmol) and4-(3-aminopropyl)morpholine (0.47 mL, 3.22 mmol) in 2-pentanol (10 mL)was stirred at reflux for 16 hours. The solvent was removed underreduced pressure, then the residue was diluted with aqueous Na₂ CO₃ (50mL) and extracted with EtOAc (3×50 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with 3-5% MeOH/CH₂Cl₂, gave a crude product, which was treated with aqueous Na₂ CO₃ andextracted with CH₂ Cl₂ (3×50 mL) to give3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-morpholino)propylamino]-1H-[1,6]naphthyridin-2-one;(133 mg, 93%): mp (CH₂ Cl₂ /light petroleum) 157-159° C.

¹ H NMR (CDCl₃) δ 8.33 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.40 (d, J=7.9Hz, 2H, H-3',5'), 7.24 (dd, J=8.6, 7.6 Hz, 1H, H-4'), 6.03 (s, 1H, H-8),5.87 (br t, J=5.2 Hz, 1H, NHCH₂), 3.77 (t, J=4.7 Hz, 4H, O(CH₂)₂), 3.65(s, 3H, NCH₃), 3.45 (q, J=6.1 Hz, 2H, NHCH₂), 2.54 (t, J=6.6 Hz, 2H,NCH₂), 2.50 (br m, 4H, N(CH₂)₂), 1.87 (pentet, J 6.5 Hz, 2H, CH₂).

¹³ C NMR δ 160.77, 159.95 (2 s, C-2,7), 150.82 (d, C-5), 147.18 (s,C-8a), 138.29 (d, C-4), 135.83 (s, 2 C, C-2',6'), 134.86 (s, C-1'),129.53 (d, C-4'), 127.92 (d, 2 C, C-3',5'), 123.99 (s, C-3), 109.27 (s,C-4a), 86.73 (d, C-8), 67.02 (t, 2 C, O(CH₂)₂), 57.20 (t, NCH₂), 53.77(t, 2 C, N(CH₂)₂), 41.61 (t, NCH₂), 29.36 (q, NCH₃), 25.29 (t, CH₂).

Analysis calculated for C₂₂ H₂₄ Cl₂ N₄ O₂ requires:

C, 59.1; H, 5.4; N, 12.5%.

Found: C, 59.1; H, 5.4; N, 12.5%.

Example L Preparation of3-(2,6-dichlorophenyl)-7-[3-(imidazol-1-yl)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (107 mg, 0.33 mmol) and1-(3-aminopropyl)imidazole (0.40 mL, 3.36 mmol) in 2-pentanol (10 mL)was stirred at reflux for 16 hours. The solvent was removed underreduced pressure, then the residue was diluted with aqueous Na₂ CO₃(50mL) and extracted with EtOAc (3×50 mL). The solvent was removed, thenchromatography of the residue twice on silica gel, eluting with 3-6%MeOH(CH₂ Cl₂, gave a crude product, which was treated with aqueous Na₂CO₃ and extracted with CH₂ Cl₂ (3×50 mL) to give3-(2,6-dichlorophenyl)-7-[3-(imidazol-1-yl)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;(116 mg, 82%): mp (CH₂ Cl₂ /hexane/Et₂ O) 175-178° C.

¹ H NMR (CDCl₃) δ 8.34 (s, 1H, H-5), 7.54, 7.53 (2 s, 2H, H-4,2"), 7.39(d, J=8.1 Hz, 2H, H-3',5'), 7.24 (dd, J=8.5, 7.6 Hz, 1H, H-4'), 7.11,6.97 (2 s, 2H, H-4",5"), 6.03 (s, 1H, H-8), 5.09 (br t, J=5.8 Hz, 1H,NHCH₂), 4.11 (t, J=6.8 Hz, 2H, NCH₂), 3.61 (s, 3H, NCH₃), 3.41 (q, J=6.4Hz, 2H, NHCH₂), 2.17 (pentet, J=6.7 Hz, 2H, CH₂).

¹³ C NMR δ 160.69, 159.52 (2 s, C-2,7), 150.61 (d, C-5), 147.10 (s,C-8a), 138.17 (d, C-4), 137.18 (d, C-2'), 135.77 (s, 2 C, C-2',6'),134.72 (s, C-1), 129.83, 129.61 (2 d, C-4',4"), 127.93 (d, 2 C,C-3',5'), 124.65 (s, C-3), 118.76 (d, C-5"), 109.72 (s, C-4a), 87.76 (d,C-8), 44.32, 39.02 (2 t, 2NCH₂), 30.82 (t, CH₂), 29.39 (q, NCH₃).

Analysis calculated for C₂₁ H₁₉ Cl₂ N₅ O requires:

C, 58.9; H, 4.5; N, 16.4%.

Found: C, 58.5; H, 4.5; N, 16.0%.

Example M Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-(phenylamino)-1H-[1,6]naphthyridin-2-one

A mixture of (IX, where R² is methyl) (86 mg, 0.27 mmol) and aniline(1.0 mL, 11.0 mmol) was stirred at 175° C. for 100 minutes. Theresulting mixture was diluted with aqueous Na₂ CO₃ (50 mL) and extractedwith CH₂ Cl₂ (2×50 mL). The solvent was removed, then chromatography ofthe residue on silica gel, eluting with 1% MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-1-methyl-7-(phenylamino)-1H-[1,6]naphthyridin-2-one;(88 mg, 83%): mp (CH₂ Cl₂ /light petroleum) 237-239° C.

¹ H NMR [(CD₃)₂ SO] δ 9.52 (br s, 1H, NH), 8.59 (s, 1H, H-5), 7.89 (s,1H, H-4), 7.68 (d, J=7.7 Hz, 2H, H-2",6"), 7.58 (d, J=8.2 Hz, 2H,H-3',5'), 7.45 (dd, J=8.8, 7.5 Hz, 1H, H-4'), 7.32 (t, J=7.9 Hz, 2H,H-3",5"), 6.98 (t, J=7.3 Hz, 1H, H-4"), 6.73 (s, 1H, H-8), 3.56 (s, 3H,NCH₃).

¹³ C NMR δ 159.60, 156.99 (2 s, C-2,7), 150.07 (d, C-5), 145.91 (s,C-8a), 140.77 (s, C-1"), 138.01 (d, C-4), 134.88 (s, 2 C, C-2',6'),134.71 (s, C-1'), 130.38 (d, C-4'), 128.70 (d, 2 C, C-3",5"), 127.97 (d,2 C, C-3',5'), 124.08 (s, C-3), 121.44 (d, C-4"), 118.94 (d, 2 C,C-2",6"), 109.84 (s, C4a), 91.30 (d, C-8), 28.83 (q, NCH₃).

Analysis calculated for C₂₁ H₁₅ Cl₂ N₃ O.0.75 H₂ O requires:

C, 61.5; H, 4.0; N, 10.3%.

Found: C, 61.4; H, 3.6; N, 10.2%.

Example N Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one

A stirred solution of (IX, where R² is methyl) (100 mg, 0.31 mmol) and4-aminopyridine (87 mg, 0.93 mmol) in THF (5.0 mL) under nitrogen at-78° C. was treated with a solution of LDA in cyclohexane (1.2 mL of 1.5M, 1.8 mmol), then the temperature was allowed to rise slowly to 20° C.,and the mixture stirred at 20° C. for 2 days. The resulting solution wastreated with aqueous Na₂ CO₃ and extracted with EtOAc (4×50 mL), theninsoluble material was collected by filtration and combined with theabove extracts. The solvent was removed, then chromatography of theresidue on silica gel, eluting with 0.5-5% MeOH/EtOAc gave3-(2,6-dichlorophenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;(58 mg, 47%): mp (MeOH/CHCl₃ /light petroleum) 275-277° C.

¹ H NMR [(CD₃)₂ SO] δ 9.99 (br s, 1H, NH), 8.70 (s, 1H, H-5), 8.36 (d,J=5.8 Hz, 2H, H-3",5"), 7.98 (s, 1H, H-4), 7.71 (d, J=5.6 Hz, 2H,H-2",6"), 7.59 (d, J=8.1 Hz, 2H, H-3',5'), 7.47 (dd, J=8.8, 7.4 Hz, 1H,H-4'), 6.86 (s, 1H, H-8), 3.60 (s, 3H, NCH₃).

¹³ C NMR δ 159.55, 156.01 (2 s, C-2,7), 149.93 (d, 2 C, C-3",5"), 149.78(d, C-5), 147.44 (s, C-1"), 145.96 (s, C-8a), 137.97 (d, C-4), 134.80(s, 2 C, C-2',6'), 134.51 (s, C-1'), 130.58 (d, C-4'), 128.05 (d, 2 C,C-3',5'), 125.58 (s, C-3), 112.25 (d, 2 C, C-2",6"), 110.87 (s, C-4a),93.79 (d, C-8), 29.03 (q, NCH₃).

Analysis calculated for C₂₀ H₁₄ Cl₂ N₄ O.0.5CH₃ OH requires:

C, 59.6; H, 3.9; N, 13.6%.

Found: C, 59.8; H, 3.8; N, 13.8% (MeOH detected by NMR)

Example O Preparation of3-(2,6-dichlorophenyl)-7-[(4-methoxyphenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one

A mixture of (IX, where R² is methyl) (200 mg, 0.62 mmol) andp-anisidine (1.46 g, 11.9 mmol) was stirred at 175° C. for 4 hours. Theresulting mixture was diluted with aqueous Na₂ CO₃ (50 mL) and extractedwith CH₂ Cl₂ (3×50 mL). The solvent was removed, then successivechromatography of the residue on silica gel (3×), eluting with 0-1%MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-7-[(4-methoxyphenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;(99 mg, 38%): mp (CH₂ Cl₂ /light petroleum) 173-175° C.

¹ H NMR (CDCl₃) δ 8.39 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=8.1Hz 2H, H-3',5'), 7.30 (d, J=8.9 Hz, 2H, H-2",6"), 7.24 (dd, J=8.6, 7.7Hz, 1H, H-4'), 6.97 (d, J=8.8 Hz, 2H, H-3",5"), 6.95 (br s, 1H, NH),6.40 (s, 1H, H-8), 3.85 (s, 3H, OCH₃), 3.54 (s, 3H, NCH₃).

¹³ C NMR δ 160.67, 158.79 (2 s, C-2,7), 157.24 (s, C-4"), 150.74 (d,C-5), 147.23 (s, C-8a), 138.00 (d, C-4), 135.77 (s, 2 C, C-2',6'),134.71 (s, C-1'), 131.88 (s, C-1"), 129.63 (d, C-4'), 127.94 (d, 2 C,C-3',5'), 125.24 (d, 2 C, C-2",6"), 125.03 (s, C-3), 114.95 (d, 2 C,C-3",5"), 110.25 (s, C-4a), 87.97 (d, C-8), 55.53 (q, OCH₃), 29.41 (q,NCH₃).

Analysis calculated for C₂₂ H₁₇ Cl₂ N₃ O₂ requires:

C, 62.0; H, 4.0; N, 9.9%.

Found: C, 61.8; H, 3.9; N, 10.1%

Example P Preparation of3-(2,6-dichlorophenyl)-7-[(4-(2-(diethylamino)ethoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one

A mixture of (IX, where R² is methyl) (100 mg, 0.31 mmol) and4-[2-(diethylamino)ethoxy]aniline (1.18 g, 5.67 mmol) was stirred at170° C. for 2.5 hours. The resulting mixture was diluted with aqueousNa₂ CO₃ (50 mL) and extracted with CH₂ Cl₂ (4×50 mL). The solvent wasremoved, then chromatography of the residue twice on alumina, elutingwith 0.25% MeOR/CH₂ Cl₂, gave a crude oil. This was further purified bypreparative reversed-phase (C-18) HPLC (56% CH₃ CN/aqueous HCO₂ NH₄buffer, pH 4.5), then by chromatography on alumina (due to partialoxidation during previous purification), eluting with 1% MeOH/CH₂ Cl₂,to give3-(2,6-dichlorophenyl)-7-[(4-(2-(diethylamino)ethoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;(31 mg, 20%): mp (hexane/Et₂ O) 149-150° C.

¹ H NMR (CDCl₃) δ 8.40 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=8.0Hz, 2H, H-3',5'), 7.28 (d, J=8.9 Hz, 2H, H-2",6"), 7.25 (dd, J=8.5, 7.6Hz, 1H, H-4'), 6.97 (d, J=8.9 Hz, 2H, H-3",5"), 6.67 (br s, 1H, NH),6.39 (s, 1 H, H-8), 4.09 (t, J=6.2 Hz, 2H, OCH₂), 3.54 (s, 3H, NCH₃),2.91 (t, J=6.2 Hz, 2H, NCH₂), 2.67 (q, J=7.1 Hz, 4H, N(CH₂)₂), 1.09 (t,J=7.1 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.67, 158.79 (2 s, C-2,7), 156.55 (s, C-4"), 150.72 (d,C-5), 147.24 (s, C-8a), 138.00 (d, C-4), 135.77 (s, 2 C, C-2',6'),134.72 (s, C-1'), 131.84 (s, C-1"), 129.63 (d, C-4'), 127.95 (d, 2 C,C-3',5'), 125.25 (d, 2 C, C-2",6"), 125.05 (s, C-3), 115.58 (d, 2 C,C-3",5"), 110.26 (s, C-4a), 87.99 (d, C-8), 66.84 (t, OCH₂), 51.72 (t,NCH₂), 47.83 (t, 2 C, N(CH₂)₂), 29.41 (q, NCH₃), 11.74 (q, 2 C, 2CH₃).

Analysis calculated for C₂₇ H₂₈ Cl₂ N₄ O₂ requires:

C, 63.4; H, 5.5; N, 11.0%.

Found: C, 63.5; H, 5.8; N, 11.1%.

Example Q Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-morpholino)butylamino]-1H-[1,6]naphthyridin-2-one

A solution of (IX, where R² is methyl) (100 mg, 0.31 mmol) and4-(4-aminobutyl)morpholine (0.50 g, 3.16 mmol) in 2-pentanol (10 mL) wasstirred at reflux for 15 hours. The solvent was removed under reducedpressure, then the residue was diluted with aqueous Na₂ CO₃ (50 mL) andextracted with EtOAc (5×50 mL). The solvent was removed, thenchromatography of the residue three times on silica gel, eluting with2.5-4% MeOH/CH₂ Cl₂, gave a crude product, which was treated withaqueous Na₂ CO₃ and extracted with CH₂ Cl₂ (4×50 mL) to give3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-morpholino)butylamino]-1H-[1,6]naphthyridin-2-one;(135 mg, 95%): foam.

¹ H NMR (CDCl₃) δ 8.32 (s, 1H, H-5), 7.52 (s, 1H, H-4), 7.39 (d, J=8.1Hz, 2H, H-3',5'), 7.24 (dd, J=8.6, 7.7 Hz, 1H, H-4'), 6.02 (s, 1H, H-8),5.48 (br s, 1H, NHCH₂), 3.75 (t, J=4.6 Hz, 4H, O(CH₂)₂), 3.65 (s, 3H,NCH₃), 3.36 (br t, J=6.6 Hz, 2H, NHCH₂), 2.47 (br m, 4H, N(CH₂)₂), 2.41(t, J=7.1 Hz, 2H, NCH₂), 1.76, 1.66 (2 pentet, J=7.0 Hz, 2×2H, 2CH₂).

¹³ C NMR δ 160.76, 159.85 (2 s, C-2,7), 150.76 (d, C-5), 147.18 (s,C-8a), 138.27 (d, C-4), 135.81 (s, 2 C, C-2',6'), 134.84 (s, C-1'),129.52 (d, C-4'), 127.89 (d, 2 C, C-3',5'), 123.97 (s, C-3), 109.23 (s,C-4a), 86.61 (d, C-8), 66.88 (t, 2 C, O(CH₂)₂), 58.37 (t, NCH₂), 53.66(t, 2 C, N(CH₂)₂), 42.36 (t, NCH₂), 29.34 (q, NCH₃), 27.02, 24.11 (2 t,2CH₂).

Analysis calculated for C₂₃ H₂₆ Cl₂ N₄ O₂ H₂ O requires:

C, 57.6; H, 5.9; N, 11.7%.

Found: C, 57.3; H, 5.6; N, 11.5%.

Example R Preparation of3-(2,6-dichlorophenyl)-7-[(4-(3-(diethylamino)propoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one

A stirred solution of (IX, where R² is methyl) (82 mg, 0.25 mmol) and4-[3-(diethylamino)propoxy]aniline (0.17 g, 0.77 mmol) in THF (5.0 mL)under nitrogen at -78° C. was treated with a solution of LDA incyclohexane (1.0 mL of 1.5 M, 1.5 mmol), then the temperature wasallowed to rise slowly to 20° C., and the mixture stirred at 20° C. for43 hours. The resulting solution was treated with aqueous Na₂ CO₃ andextracted with EtOAc (4×50 mL). The solvent was removed, thenchromatography of the residue on alumina, eluting with 0.25-0.5%MeOH/CH₂ Cl₂, gave3-(2,6-dichlorophenyl)-7-[(4-(3-(diethylamino)propoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;(67 mg, 50%): mp (CH₂ Cl₂ /hexane) 151-152° C.

¹ H NMR (CDCl₃) δ 8.39 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=8.3Hz, 2H, H-3',5'), 7.27 (d, J=9.0 Hz, 2H, H-2",6"), 7.25 (dd, J=8.7, 7.7Hz, 1H, H-4'), 6.97 (d, J=9.0 Hz, 2H, H-3",5"), 6.86 (br s, 1H, NH),6.39 (s, 1H, H-8), 4.05 (t, J=6.4 Hz, 2H, OCH₂), 3.54 (s, 3H, NCH₃),2.63 (t, J=7.3 Hz, 2H, NCH₂), 2.56 (q, J=7.2 Hz, 4H, N(CH₂)₂), 1.95(pentet, J=6.8 Hz, 2H, CH₂), 1.05 (t, J=7.1 Hz, 6H, 2CH₃).

¹³ C NMR δ 160.68, 158.84 (2 s, C-2,7), 156.81 (s, C-4"), 150.76 (d,C-5), 147.24 (s, C-8a), 138.01 (d, C-4), 135.78 (s, 2 C, C-2',6'),134.73 (s, C-1'), 131.67 (s, C-1"), 129.63 (d, C-4'), 127.95 (d, 2 C,C-3',5'), 125.29 (d, 2 C, C-2",6"), 125.01 (s, C-3), 115.56 (d, 2 C,C-3",5"), 110.24 (s, C-4a), 87.92 (d, C-8), 66.71 (t, OCH₂), 49.38 (t,NCH₂), 47.00 (t, 2 C, N(CH₂)₂), 29.41 (q, NCH₃), 27.05 (t, CH₂), 11.77(q, 2 C, 2CH₃).

Analysis calculated for C₂₈ H₃₀ Cl₂ N₄ O₂ requires:

C, 64.0; H, 5.8; N, 10.7%.

Found: C, 63.9; H, 5.6; N, 11.0%.

Example S Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one

A stirred solution of (IX, where R² is methyl) (100 mg, 0.31 mmol) and4-[2-(4-methylpiperazin-1-yl)ethoxy]aniline (0.26 g, 1.12 mmol) in THF(5.0 mL) under nitrogen at -78° C. was treated with a solution of LDA incyclohexane (0.8 mL of 1.5 M, 1.2 mmol), then the temperature wasallowed to rise slowly to 20° C., and the mixture stirred at 20° C. for2.5 days. The resulting solution was cooled to -78° C. and treated withAcOH (0.5 mL), then treated at 20° C. with aqueous Na₂ CO₃ and extractedwith EtOAc (5×50 mL). The solvent was removed, then chromatography ofthe residue on alumina, eluting with CH₂ Cl₂, gave firstly recovered IX,where R² is methyl (49 mg, 49%). Further elution with 0.25-0.5% MeOH/CH₂Cl₂ gave a crude oil, which was again chromatographed on alumina,eluting with 0.25-0.3% MeOH/CH₂ Cl₂, to give3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;(27 mg, 16%): mp (CH₂ Cl₂ /hexane) 170-171.5° C.

¹ H NMR (CDCl₃) δ 8.40 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=8.4Hz, 2H, H-3',5'), 7.28 (d, J=8.9 Hz, 2H, H-2",6"), 7.25 (dd, J=8.7, 7.7Hz, 1H, H-4'), 6.97 (d, J=8.9 Hz, 2H, H-3",5"), 6.83 (br s, 1H, NH),6.40 (s, 1H, H-8), 4.14 (t, J=5.8 Hz, 2H, OCH₂), 3.54 (s, 3H, NCH₃),2.86 (t, J=5.8 Hz, 2H, NCH₂), 2.66, 2.50 (2 br s, 2×4H, N(CH₂)₄ N), 2.31(s, 3H, NCH₃).

¹³ C NMR δ 160.66, 158.71 (2 s, C-2,7), 156.43 (s, C-4"), 150.74 (d,C-5), 147.23 (s, C-8a), 137.99 (d, C-4), 135.77 (s, 2 C, C-2',6'),134.71 (s, C-1'), 131.97 (s, C-1"), 129.64 (d, C-4'), 127.95 (d, 2 C,C-3',5'), 125.17 (d, 2 C, C-2",6"), 125.08 (s, C-3), 115.66 (d, 2 C,C-3",5"), 110.29 (s, C-4a), 88.02 (d, C-8), 66.25 (t, OCH₂), 57.15 (t,NCH₂), 55.02, 53.56 (2 t, 2×2 C, N(CH₂)₄ N), 46.01 (q, NCH₃), 29.43 (q,NCH₃).

Analysis calculated for C₂₈ H₂₉ Cl₂ N₅ O₂ requires:

C, 62.5; H, 5.4; N, 13.0%.

Found: C, 62.5; H, 5.7; N, 13.1%.

Example T Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one

A stirred solution of (IX, where R² is methyl) (103 mg, 0.32 mmol) and

4-[3-(4-methylpiperazin-1-yl)propoxy]aniline (0.31 g, 1.24 mmol) in THF(5.0 mL) under nitrogen at -78° C. was treated with a solution of LDA incyclohexane (0.9 mL of 1.5 M, 1.35 mmol), then the temperature wasallowed to rise slowly to 20° C., and the mixture stirred at 20° C. for2.5 days. The resulting solution was treated with aqueous Na₂ CO₃ andextracted with EtOAc (5×50 mL). The solvent was removed, thenchromatography of the residue on alumina, eluting with 0.3-0.5% MeOH/CH₂Cl₂, gave3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;(111 mg, 63%): mp (CH₂ Cl₂ /hexane) 159-160° C.

¹ H NMR (CDCl₃) δ 8.39 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=7.8Hz, 2H, H-3',5'), 7.28 (d, J=8.8 Hz, 2H, H-2",6"), 7.25 (dd, J=8.7, 7.7Hz, 1H, H-4'), 6.96 (d, J=8.8 Hz, 2H, H-3",5"), 6.90 (br s, 1H, NH),6.40 (s, 1H, H-8), 4.05 (t, J=6.4 Hz, 2H, OCH₂), 3.54 (s, 3H, NCH₃),2.8-2.2 (br s, 8H, N(CH₂)₄ N), 2.56 (t, J=7.4 Hz, 2H, NCH₂), 2.30 (s,3H, NCH₃), 2.00 (pentet, J=6.9 Hz, 2H, CH₂).

¹³ C NMR δ 160.66, 158.79 (2 s, C-2,7), 156.69 (s, C-4"), 150.74 (d,C-5), 147.23 (s, C-8a), 138.00 (d, C-4), 135.76 (s, 2 C, C-2',6'),134.71 (s, C-1'), 131.76 (s, C-1"), 129.63 (d, C-4'), 127.94 (d, 2 C,C-3',5'), 125.23 (d, 2 C, C-2",6"), 125.01 (s, C-3), 115.55 (d, 2 C,C-3",5"), 110.24 (s, C-4a), 87.94 (d, C-8), 66.59 (t, OCH₂), 55.13 (t,3C, NCH₂,N(CH₂)₂), 53.23 (t, 2 C, N(CH₂)₂, 46.04 (q, NCH₃), 29.41 (q,NCH₃), 26.79 (t, CH₂).

Analysis calculated for C₂₉ H₃₁ Cl₂ N₅ O₂ requires:

C, 63.0; H, 5.7; N, 12.7%.

Found: C, 62.9; H, 5.7; N, 13.0%.

Example U Preparation of3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(4-methylpiperazin-1-yl)phenyl)amino]-1H-[1,6]naphthyridin-2-one

A stirred solution of (IX, where R² is methyl) (100 mg, 0.31 mmol) and4-(4-methylpiperazin-1-yl)aniline (177 mg, 0.93 mmol) in THF (5.0 mL)under nitrogen at -78° C. was treated with a solution of LDA incyclohexane (1.2 mL of 1.5 M, 1.8 mmol), then the temperature wasallowed to rise slowly to 20° C., and the mixture stirred at 20° C. for40 hours. The resulting solution was treated with aqueous Na₂ CO₃ andextracted with EtOAc (3×50 mL). The solvent was removed, thenchromatography of the residue on alumina, eluting with 0.25-0.5%MeOH/CH₂ Cl₂, then on silica gel, eluting with 2-3% MeOH/CH₂ Cl₂, gave acrude product, which was treated with aqueous Na₂ CO₃ and extracted withEtOAc (2×50 mL), to give3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(4-methylpiperazin-1-yl)phenyl)amino]-1H-[1,6]naphthyridin-2-one;(56 mg, 37%): mp (CH₂ Cl₂ /hexane) 153-161° C.

¹ H NMR (CDCl₃) δ 8.40 (s, 1H, H-5), 7.55 (s, 1H, H-4), 7.40 (d, J=7.8Hz, 2H, H-3',5'), 7.26 (d, J=9.0 Hz, 2H, H-2",6"), 7.25 (dd, J=8.6, 7.6Hz, 1H, H-4'), 6.99 (d, J=9.0 Hz, 2H, H-3",5"), 6.68 (br s, 1H, NH),6.43 (s, 1H, H-8), 3.54 (s, 3H, NCH₃), 3.25 (t, J=5.0 Hz, 4H, N(CH₂)₂),2.62 (t, J=4.9 Hz, 4H, N(CH₂)₂), 2.38 (s, 3H, NCH₃).

¹³ C NMR δ 160.68, 158.69 (2 s, C-2,7), 150.75 (d, C-5), 148.86 (s,C-4"), 147.22 (s, C-8a), 138.01 (d, C-4), 135.78 (s, 2 C, C-2',6'),134.74 (s, C-1'), 130.93 (s, C-1"), 129.61 (d, C-4'), 127.94 (d, 2 C,C-3',5'), 124.93 (s, C-3), 124.66 (d, 2 C, C-2",6"), 117.06 (d, 2 C,C-3",5"), 110.21 (s, C-4a), 87.95 (d, C-8), 55.03 (t, 2 C, N(CH₂)₂),49.14 (t, 2 C, N(CH₂)₂), 46.05 (q, NCH₃), 29.44 NCH₃).

Analysis calculated for C₂₆ H₂₅ Cl₂ N₅ O.0.5 H₂ O requires:

C, 62.0; H, 5.2; N, 13.9%.

Found: C, 61.8; H, 5.3; N, 13.5%

Example V Preparation of 7-fluoro-1-ethyl-1H-[1,6]naphthyridin-2-one

A solution of (IV) (1.0 g, 7.3 mmol) in dioxane (10 mL) was treated withcarbethoxymethylene triphenyl phosphorane (5.1 g, 14.7 mmol) and heatedto a gentle reflux for 2.5 hours. The cooled reaction mixture wasrapidly filtered through a pad of silica gel eluting with 0% to 5%methanol in ethyl acetate. Evaporation of the solvent andrecrystallization (1:1 methylene chloride/ethyl acetate) of theresulting residue gave ethyl 3-(4,6-diamino-3-pyridyl) acrylate (XI) asa solid (0.72 g, 48%): mp 151-152° C.

¹ H NMR [(CD₃)₂ SO] δ 8.01 (s, 1H, H-2), 7.68 (d, 1H, J=15.9 Hz), 6.17(d, 1H, J=15.9 Hz), 5.99, 5.87 (2 br s, 2×2H, 2NH₂), 5.62 (s, 1H, H-5),4.13 (q, 2H, J=7.23 Hz, CH₂), 1.23 (t, 3H, J=7.23 Hz, CH₃).

Analysis calculated for C₁₀ H₁₃ N₃ O₂ requires:

C, 57.96; H, 6.32; N, 20.28%.

Found: C, 57.90; H, 6.21; N, 20.34%.

A suspension of (XI) (4.7 g, 22.7 mmol) in1,8-diazabicyclo[5.4.0]undec-7-ene (22 mL) was heated to 165° C. undernitrogen for 16 hours. The 1,8-diazabicyclo[5.4.0]undec-7-ene wasdistilled under vacuum to leave a residue that was triturated in hothexanes (2×100 mL). The solid was then triturated in hot 5:1 ethylacetate: methanol to provide an off-white solid that was filtered andwashed with ethyl acetate. The filtrates were concentrated, purified bysilica gel chromatography, and further processed as above to leaveadditional product. The crops were combined to give7-amino-1H-[1,6]naphthyridin-2-one (XII) (2.55 g 70%): mp >275° C.

¹ H NMR [(CD₃)2SO] δ 11.42 (bs, 1H, NHC=O), 8.24 (s, 1H, H-5), 7.68 (d,1H, J=9.40 Hz), 6.37 (bs, 2H, NH₂), 6.13 (s, 1H, H-8), 6.06 (d, 1H,J=9.40 Hz).

MS (APCI) m/z 162 (M+H, 100%).

To a stirred solution of (XII) (2.1 g, 13 mmol) in dry DMF (65 mL) wasadded cesium carbonate (6.4 g, 19.6 mmol), followed by ethyl iodine(1.71 mL, 21.4 mmol), and the mixture was stirred at 60° C. for 4.5hours. The cooled mixture was filtered, and the filtrate was dilutedwith ethyl acetate. The solution was washed with brine, dried, andconcentrated to give an orange residue that was purified by silica gelchromatography, eluting with 1:1 ethyl acetate: hexanes and then ethylacetate. Concentration of product fractions gave7-amino-1-ethyl-1H-[1,6]naphthyridin-2-one (XIII) (1.3 g, 53%).

¹ H NMR [(CD₃)₂ SO] δ 8.23 (s, 1H, H-5), 7.64 (d, 1H, J=9.28 Hz), 6.40(bs, 2H, NH₂), 6.26 (s, 1H, H-8), 6.11 (d, 1H, J=9.28 Hz), 3.98 (q, 2H,J=7.08 Hz, CH₂), 1.11 (t, 3H, J=7.08 Hz, CH₃).

A suspension of (XIII) (1.1 g, 5.8 mmol) in 48% aqueous HBF₄ (20 mL) at-10° C. was treated with NaNO₂ (0.44 g, 6.38 mmol, added in smallportions over 3 hours). The resulting mixture was neutralized (pH 7)with solid Na₂ CO₃ carefully, keeping the temperature below 0° C., andextracted with EtOAc (3×75 mL). The solvent was removed, thenchromatography of the residue on silica gel, eluting with ethyl acetate,gave 7-fluoro-1-ethyl-1H-[1,6]naphthyridin-2-one (XV) (0.72 g, 64%).

¹ H NMR [(CD₃)₂ SO] δ 8.57 (s, 1H, H-5), 7.95 (d, 1H, J=9.52 Hz), 7.30(s, 1H, H-8), 6.11 (d, 1H, J=9.52 Hz), 4.15 (q, 2H, J=7.08 Hz, CH₂.),1.12 (t, 3H, J=7.08 Hz, CH₃).

MS (APCI) m/z 193 (M+H, 100%).

Example W Preparation of1-ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one

A stirred solution of (XV, where R² is ethyl) (100 mg, 0.52 mmol) andaniline (120 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. wastreated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide(1.5 M in cyclohexane), then the temperature was allowed to rise slowlyto 20° C. overnight. The resulting solution was treated with 3 drops ofglacial acetic acid and concentrated to a brown residue that waspurified by silica gel chromatography eluting with EtOAc. The productfractions were pooled and concentrated to a solid that was crystallizedto give 1-ethyl-7-phenylamino-1H -[1,6]naphthyridin-2-one (33 mg, 24%):mp (8:1 hexanes/dichloromethane) 174-175° C.

¹ H NMR [(CD₃)₂ SO] 67 9.37 (bs, 1H, NH), δ 8.52 (s, 1H, H-5), 7.81 (d,1H, J=9.40 Hz), 7.66 (d, 2H, J=8.44 Hz,), 7.30 (t, 2H, J=7.47 Hz) 6.95(t, 1H, J=7.47 Hz) 6.72 (s, 1H) 6.32 (d, 1H, J=9.40 Hz), 4.10 (q, 2H,J=7.23 Hz, CH₂), 1.23 (t, 3H, J=7.23 Hz, CH₃).

IR (KBR) 1624cm⁻¹.

MS (APCI) m/z 266.1.

Analysis calculated for C₁₆ H₁₅ N₃ O.0.30 H₂ O requires:

C, 70.99; H, 5.81; N, 15.52%.

Found: C, 71.01; H, 5.62; N, 15.35%.

Example X Preparation of1-ethyl-7-(4-methoxyphenylamino)-1H-[1,6]naphthyridin-2-one

A stirred solution of (XV, where R² is ethyl) (100 mg, 0.52 mmol) andp-anisidine (160 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C.was treated with a solution (1.2 mL, 1.8 mmol) of lithiumdiisopropylamide (1.5 M in cyclohexane), then the temperature wasallowed to rise slowly to 20° C. overnight. The resulting solution wastreated with 3 drops of glacial acetic acid and concentrated to a brownresidue that was purified by silica gel chromatography eluting with 1:1EtOAc hexanes then EtOAc. The product fractions were pooled andconcentrated to a solid that was crystallized to give1-ethyl-7-(4-methoxyphenylamino)-1H -[1,6]naphthyridin-2-one (87 mg,57%): mp (2-propanol) 165-166° C.

¹ H NMR [(CD₃)₂ SO] δ 9.17 (bs, 1H, NH), δ 8.46 (s, 1H, H-5), 7.77 (d,1H, J=9.40 Hz), 7.52 (d, 2H, J=8.92 Hz,), 6.90 (d, 2H, J=8.92 Hz) 6.59(s, 1H ) 6.28 (d, 1H, J=9.40 Hz), 4.07 (q, 2H, J=6.99 Hz, CH₂), 1.20 (t,3H, J=6.99 Hz, CH₃).

IR(KBR) 1619 cm⁻¹.

MS (APCI) m/z 296.0.

Analysis calculated for C₁₇ H₁₇ N₃ O₂ requires:

C, 69.14; H, 5.80; N, 14.23%.

Found: C, 69.14; H, 5.84; N, 13.99%.

Example Y Preparation of1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one

A stirred solution of (XV, where R² is ethyl) (100 mg, 0.52 mmol),4-(4-methyl-1-piperazinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL)under nitrogen at -78° C. was treated was treated with a solution (0.8mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), thenthe temperature was allowed to rise slowly to 20° C. overnight. Theresulting solution was treated with 3 drops of glacial acetic acid andconcentrated to a dark residue that was purified by silica gelchromatography eluting with 90:9:1 EtOAc:MeOH:NH₄ OH. The productfractions were pooled and concentrated to a solid that was triturated inboiling hexanes. The solid was collected and crystallized to give1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one(84 mg, 44%): mp (CH₂ Cl₂ /hexanes) 188-189° C.

¹ H NMR [(CD₃)₂ SO] δ 9.10 (bs, 1H, NH), δ 8.44 (s, 1H, H-5), 7.76 (d,1H, J=9.40 Hz), 7.45 (d, 2H, J=8.92 Hz, ), 6.91 (d, 2H, J=9.16 Hz) 6.57(s, 1H) 6.26 (d, 1H, J=9.40 Hz), 4.08 (q, 2H, J=6.99 Hz, CH₂), 3.05-3.08(m, 4H, CH₂), 2.44-2.46 (m, 4H, CH₂), 2.22 (s, 3H, NCH₃), 1.20 (t, 3H,J=6.99 Hz, CH₃).

IR (KBR) 1619 cm⁻¹.

MS (APCI) m/z 364.2.

Analysis calculated for C₂₁ H₂₅ N₅ O₁ 0.7 H₂ O requires:

C, 67.07; H, 7.08; N, 18.62%.

Found: C, 67.22; H, 6.70; N, 18.39%.

Example Z Preparation of 1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one

A stirred solution of (XV, where R² is ethyl) (100 mg, 0.52 mmol),4-(4-morpholinyl)aniline (0.26 g, 1.1 mmol) in THF (5.0 mL) undernitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) oflithium diisopropylamide (1.5 M in cyclohexane), then the temperaturewas allowed to rise slowly to 20° C. overnight. The resulting solutionwas treated with 3 drops of glacial acetic acid and concentrated to adark residue that was purified that purified by silica gelchromatography eluting with EtOAc. The product fractions were pooled andconcentrated to a solid that was crystallized to give1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one (94mg, 52%): mp (2-propanol/hexanes) 219-223° C.

¹ H NMR [(CD₃)₂ SO] δ 9.13 (bs, 1H, NH), δ 8.45 (s, 1H, H-5), 7.77 (d,1H, J=9.40 Hz), 7.48 (d, 2H, J=8.92 Hz, ), 6.92 (d, 2H, J=8.92 Hz) 6.58(s, 1H) 6.27 (d, 1H, J=9.40 Hz), 4.06 (q, 2H, J=6.99 Hz, CH₂), 3.68-3.78(m, 4H, CH₂), 3.06-3.03 (m, 4H, CH₂), 1.20 (t, 3H, J=6.99 Hz, CH₃).

IR (KBR) 1619 cm⁻¹.

MS (APCI) m/z 351.2

Analysis calculated for C₂₀ H₂₂ N₄ O₂.0.3 H₂ O requires:

C, 67.44; H, 6.41; N, 15.73%.

Found: C, 67.45; H, 6.16; N, 15.35%.

Example AA Preparation of 1-ethyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one

A stirred solution of (XV, where R² is ethyl) (100 mg, 0.52 mmol),4-(1-piperidinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) undernitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) oflithium diisopropylamide (1.5 M in cyclohexane), then the temperaturewas allowed to rise slowly to 20° C. overnight. The resulting solutionwas treated with 3 drops of glacial acetic acid and concentrated to adark residue that was purified that purified by silica gelchromatography eluting with EtOAc. The product fractions were pooled andconcentrated to a foam that was crystallized to giveethyl-7-(4-(piperidin-1-yl)phenylamino)-1H -[1,6]naphthyridin-2-one (79mg, 44%): mp (CH₂ Cl₂ /hexanes) 137-139° C.

¹ H NMR [(CD₃)₂ SO] δ 9.09 (bs, 1H, NH), δ 8.44 (s, 1H, H-5), 7.76 (d,1H, J=9.40 Hz), 7.43 (d, 2H, J=8.92 Hz, ), 6.90 (d, 2H, J=9.16 Hz) 6.57(s, 1H) 6.26 (d, 1H, J=9.16 Hz), 4.06 (q, 2H, J=6.99 Hz, CH₂), 3.03-3.06(m, 4H, CH₂ NCH₂), 1.66-1.60 (m, 4H, CH₂), 1.50-1.54 (m, 2H, CH₂), 1.20(t, 3H, J=6.99 Hz, CH₃).

IR (KBR) 1620 cm⁻¹.

MS (APCI) m/z 349.2.

Analysis calculated for C₂₁ H₂₄ N₄ O₁.0.2 H₂ O requires:

C, 71.65; H, 6.99; N, 15.91%.

Found: C, 71.72; H, 6.81; N, 15.93%.

Example BB Preparation of 1-ethyl-7-phenylamino-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A suspension of 1-ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one fromExample W (75 mg, 0.29 mmol), 0.6 g of Raney nickel, and 50 mL ofethanol was stirred under 50 psi of hydrogen at room temperature for 23hours. The suspension was filtered and the filtrate was concentrated toa solid residue that was purified by preparative thin layerchromatography to give1-ethyl-7-phenylamino-3,4-dihydro-1H-[1,6]naphthyridin-2-one (10 mg, 13%yield): mp 137-138° C.

¹ H NMR [(CD₃)₂ SO] δ 1.10 (t, 3H, J=7 Hz), 2.50 (t, 2H, J=7Hz), J=7Hz), 3.76 (q, 2H, J=7 Hz), 6.47, (s, 1H ), 6.79 (t, 1H, J=7 Hz), 7.18(t, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 7.89 (s, 1H), 8.89 (s, 1H).

MS (APCI) m/z 268 (M+1)

Analysis calculated for C₁₆ H₁₇ N₃ O.0.10 H₂ O.0.15C₄ H₈ O₂ requires:

C, 70.62; H, 6.57; N, 14.88

Found: C, 70.90; H, 6.26; N, 14.56.

Purification of Tyrosine Kinases

Epidermal Growth Factor Receptor (EGFr). Human EGF receptor tyrosinekinase is isolated from A431 human epidermoid carcinoma cells by thefollowing method. Cells were grown in roller bottles in 50% Dulbecco'sModified Eagle medium and 50% HAM F-12 nutrient media (Gibco) containing10% fetal calf serum. Approximately 10⁹ cells are lysed in two volumesof buffer containing 20 mM2-(4N-[2-hydroxymethyl]piperazin-1-yl)ethanesulfonic acid (Hepes), pH7.4, 5 mM ethylene glycol bis(2-aminoethyl ether) N,N,N',N'-tetraaceticacid (EGTA), 1% Triton X-100, 10% glycerol, 0.1 mM sodium orthovanadate,5 mM sodium fluoride, 4 mM pyrophosphate, 4 mM benzamide, 1 mMdithiothreitol (DTT), 80 μg/mL aprotinin, 40 μg/mL leupeptin, and 1 mMphenylmethylsulfonyl fluoride (PMSF). After centrifugation at 25,000×gfor 10 minutes, the supernatant is applied to a fast Q sepharose column(Pharmacia) and eluted with a linear gradient from 0.1 M NaCl to 0.4 MNaCl in 50 mM Hepes, 10% glycerol, pH 7.4. Enzyme active fractions arepooled, divided into aliquots, and stored at -100° C.

Platelet Derived Growth Factor Receptor (PDGFr) and Fibroblast GrowthFactor Receptor (FGFr). Full length cDNAs for the mouse PDGF-β and humanFGF-1 (flg) receptor tyrosine kinases were obtained from J. Escobedo andare prepared as described in J. Biol. Chem., 1991;262:1482-1487. PCRprimers are designed to amplify a fragment of DNA that codes for theintracellular tyrosine kinase domain. The fragment is melded into abaculovirus vector, cotransfected with AcMNPV DNA, and the recombinantvirus isolated. SF9 insect cells are infected with the virus tooverexpress the protein, and the cell lysate is used for the assay.

Other Kinases. c-Src kinase is purified from baculovirus infected insectcell lysates using an antipeptide monoclonal antibody directed againstthe N-terminal 2-17 amino acids as described previously by Fry, et al.,Anticancer Drug Design, 1994;9:331-351. Protein kinase C (PKC.) isobtained as a rat brain preparation from Promega.

Kinase Assays

EGFr. Enzyme assays for IC₅₀ determinations are performed in 96-wellfilter plates (Millipore MADVN6550). The total volume is 0.1 mLcontaining 20 mM Hepes, pH 7.4, 50 μM sodium vanadate, 40 mM magnesiumchloride, 10 μM ATP containing 0.5 μCi of [³² P]ATP, 20 μg ofpolyglutamic acid/tyrosine (Sigma Chemical Co., St. Louis, Mo.), 10 ngof EGF receptor tyrosine kinase and appropriate dilutions of inhibitor.All components except the ATP are added to the well, and the plate isincubated with shaking for 10 minutes at 25° C. The reaction is startedby adding [³² P]ATP, and the plate is incubated at 25° C. for 10minutes. The reaction is terminated by addition of 0.1 mL of 20%trichloroacetic acid (TCA). The plate is kept at 4° C. for at least 15minutes to allow the substrate to precipitate. The wells are then washedfive times with 0.2 mL of 10% TCA, and ³² P incorporation is determinedwith a Wallac beta plate counter.

PDGFr and FGFr. The assay is performed in 96-well plates (100μL/incubation/well), and conditions are optimized to measure theincorporation of ³² P from [γ³² P]ATP into a glutamate-tyrosinecopolymer substrate. Briefly, to each well is added 82.5 μL ofincubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1%Triton X-100, 0.2 mM PMSF, 0.2 mM sodium vanadate, 10 mM manganesechloride, and 750 μg/mL of poly (4:1) glutamate-tyrosine followed by 2.5μL of inhibitor and 5 μL of enzyme lysate (7.5 μg/μL FGFR-TK or 6.0μg/μL PDGFR-TK) to initiate the reaction. Following a 10 minuteincubation at 25° C., 10 μL of [γ³² P]ATP (0.4 μCi plus 50 μM ATP) isadded to each well, and samples are incubated for an additional 10minutes at 25° C. The reaction is terminated by the addition of 100 μLof 30% trichloroacetic acid (TCA) containing 20 mM sodium pyrophosphateand precipitation of material onto glass fiber filter mats (Wallac).Filters are washed three times with 15% TCA containing 100 mM sodiumpyrophosphate and the radioactivity retained on the filters counted in aWallac 1250 Betaplate reader. Nonspecific activity is defined asradioactivity retained on the filters following incubation of sampleswith buffer alone; (no enzyme). Specific enzymatic activity is definedas total activity (enzyme plus buffer) minus nonspecific activity. Theconcentration of a compound that inhibited specific activity by 50%(IC₅₀) is determined based on the inhibition curve.

c-Src. The antibody, covalently linked to 0.65-μm latex beads, is addedto a suspension of insect cell lysis buffer comprised of 150 mM NaCl, 50mM Tris pH 7.5, 1 mM DTT, 1% NP-40, 2 mM EGTA, 1 mM sodium vanadate, 1mM PMSF, 1 μg/mL each of leupeptin, pepstatin, and aprotinin. Insectcell lysate containing the c-Src protein is incubated with these beadsfor 3 to 4 hours at 4° C. with rotation. At the end of the lysateincubation, the beads are rinsed three times in lysis buffer,resuspended in lysis buffer containing 10% glycerol, and frozen. Theselatex beads are thawed, rinsed three times in assay buffer which iscomprised of 40 mM tris pH 7.5, 5 mM magnesium chloride, and suspendedin the same buffer. In a Millipore 96-well plate with a 0.65 μmpolyvinylidine membrane bottom are added the reaction components: 10-μLc-Src beads, 10 μL of 2.5 mg/mL polyglutamate-tyrosine substrate, 5 μMATP containing 0.2 μCi labeled ³² P-ATP, 5 μL DMSO containing inhibitorsor as a solvent control, and buffer to make the final volume 125 μL. Thereaction is started at room temperature by addition of the ATP andquenched 10 minutes later by the addition of 125 μL of 30% TCA, 0.1 Msodium pyrophosphate for 15 minutes on ice. The plate is then filteredand the wells washed with two 250-μL aliquots of 15% TCA, 0.1 Mpyrophosphate. The filters are punched, counted in a liquidscintillation counter, and the data examined for inhibitory activity incomparison to a known inhibitor such as erbstatin. The method isdescribed more fully in J. Med. Chem., 1994;37:598-609.

Cascade Assay for Inhibitors of the MAP Kinase Pathway (APK Assay)

Incorporation of ³² P into myelin basic protein (MBP) is assayed in thepresence of a glutathione; S-transferase fusion protein containingp44MAP kinase (GST-MAPK) and a glutathione; S-transferase fusion proteincontaining p45MEK (GST-MEK). The assay solution contains 20 mM HEPES, pH7.4, 10 mM magnesium chloride, 1 mM manganese chloride, 1 mM EGTA, 50 μM[γ³² P]ATP, 10 μg GST-MEK, 0.5 μg GST-MAPK and 40 μg MBP in a finalvolume of 100 μL. Reactions are stopped after 20 minutes by addition oftrichloroacetic acid and filtered through a GF/C filter mat. ³² Pretained on the filter mat is determined using a 1205 betaplate.Compounds are assessed at 10 μM for ability to inhibit incorporation of³² P.

To ascertain whether compounds are inhibiting GST-MEK or GST MAPK, twoadditional protocols are employed. In the first protocol, compounds areadded to tubes containing GST-MEK, followed by addition of GST-MAPK, MBPand [γ³² P]ATP. In the second protocol, compounds are added to tubescontaining both GST-MEK and GST-MAPK, followed by MBP and [γ³² P]ATP.

Compounds that show activity in both protocols are scored as MAPKinhibitors, while compounds showing activity in only the first protocolare scored as MEK inhibitors.

Other Kinases. An assay using the intracellular kinase domains ofinsulin receptor (INSr) is performed as described for the EGF receptorexcept that 10 mM manganese chloride is included in the reaction. ThePKC assay is performed as previously described by Martiny-Baron, et al.,J. Biol. Chem., 1993;268:9194-9197.

                  TABLE 1                                                         ______________________________________                                        Inhibition of Protein Kinases                                                        IC.sub.50 (μM)                                                      Example                                                                              c-Src   FGFr    PDGFr EGFr   INSr APK  PKC                             ______________________________________                                        A      0.35    0.28    2.5   -50    ND   ND   50                                B 0.42 0.34 3.6 ND ND ND ND                                                   C >50 >50 >50 ND >50 ND ND                                                    D 13 3.7 16 ND ND ND ND                                                       E 0.30 0.22 4.0 ND ND ND ND                                                   F 0.04 0.07 0.42 3.8 >50 >10 >50                                              G 0.02 0.07 0.69 ND ND ND ND                                                  H 0.06 0.05 0.89 3.2 >50   10 <50                                             I 0.04 0.10 0.95 ND ND ND ND                                                  J 0.03 0.09 0.85 ND ND ND ND                                                  K 0.36 0.31 4.7 <50 ND ND >50                                                 L 0.54 0.35 1.7 ND ND ND ND                                                   M 0.79 1.3 1.0 <50 ND ND >50                                                  N 0.55 3.3 9.6 ND ND ND ND                                                    O 1.7 1.2 1.7 ND ND ND ND                                                     P 0.08 0.06 0.09 0.59 >50 ND >50                                              Q 0.05 0.32 3.1 ND ND ND ND                                                   R 0.03 0.18 0.37 ND ND ND ND                                                  S 0.02 0.15 0.34 ND ND ND ND                                                  T 0.03 0.19 0.37 ND ND ND ND                                                  U 0.02 0.06 0.26 ND ND ND ND                                                  W >50 17 >50 ND ND ND ND                                                      X >50 10.4 5 to 50 ND ND ND ND                                                Y 11.41 1.4 5.6 ND ND ND ND                                                   Z 31 5.7 >50 ND ND ND ND                                                      AA <50 12.4 >50 ND ND ND ND                                                 ______________________________________                                         ND = Not determined.                                                     

Cell Culture

PDGF Receptor Autophosphorylation Assay. Rat aorta smooth muscle cells(RASMC.) are isolated from the thoracic aorta of rats and explantedaccording to the method of Ross, J. Cell. Biol., 1971;30:172-186. Cellsare grown in Dulbecco's modified Eagle's medium (DMEM, Gibco) containing10% fetal calf serum (FBS, Hyclone, Logan, Utah), 1% glutamine (Gibco),and 1% penicillin/streptomycin (Gibco). Cells are identified as smoothmuscle cells by their "hill and valley" growth pattern and byfluorescent staining with a monoclonal antibody specific for SMC μ-actin(Sigma). RASMC are used between passages 5 and 20 for all experiments.Test compounds are prepared in dimethylsulfoxide (DMSO) in order toachieve consistency in the vehicle and to ensure compound solubility.Appropriate DMSO controls are simultaneously evaluated with the testcompounds.

Rat aortic smooth muscle cells are grown to confluency in 100 mm dishes.Growth medium is removed and replaced with serum-free medium, and cellsare incubated at 37° C. for an additional 24 hours. Test compounds arethen added directly to the medium and cells incubated for an additional2 hours. After 2 hours, PDGF-BB is added at a final concentration of 30ng/mL for 5 minutes at 37° C. to stimulate autophosphorylation of PDGFreceptors. Following growth factor treatment, the medium is removed, andcells are washed with cold phosphate-buffered saline and immediatelylysed with 1 mL of lysis buffer (50 mM Hepes, pH 7.5, 150 mM NaCl, 10%glycerol, 1% Triton-X 100, 1 mM EDTA, 1 mM EGTA, 50 mM NaF, 1 mM sodiumorthovanadate, 30 mM p-nitrophenyl phosphate, 10 mM sodiumpyrophosphate, 1 mM phenylmethyl sulfonyl fluoride, 10 μg/mL aprotinin,and 10 μg/mL leupeptin). Lysates are centrifuged at 10,000×g for 10minutes. Supernatants are incubated with 10 μL of rabbit anti-human PDGFtype AB receptor antibody (1:1000) for 2 hours. Following theincubation, protein-A-sepharose beads are added for 2 hours withcontinuous mixing, and immune complexes bound to the beads washed fourtimes with 1 mL lysis wash buffer. Immune complexes are solubilized in40 μL of Laemmli sample buffer and electrophoresed in 8% to 16% SDSpolyacrylamide gels. Following electrophoresis, separated proteins aretransferred to nitrocellulose and immunoblotted with a 1:1000 dilutionof anti-phosphotyrosine monoclonal antibody (UBI clone; 4G10; #05-321).Following extensive washing with PBS-0.2% tween-20, the blots areincubated with horseradish peroxidase labeled goat anti-mouse IgG(1:5000; Bio-Rad Inc., Hercules, Calif.), and protein levels aredetected by enhanced chemiluminescence (ECL) detection system accordingto the instructions of the supplier (Amersham Inc., Arlington Heights,Ill.). The density of the protein bands are determined using NIH Imagesoftware (v. 1.56) and IC₅₀ values are generated from the densitometricdata.

                  TABLE 2                                                         ______________________________________                                        Inhibition of PDGF-Stimulated Receptor Autophosphorylation                             Example  IC.sub.50 (μM)                                           ______________________________________                                               F      0.49                                                              H >10                                                                         P 0.23                                                                        S 0.81                                                                      ______________________________________                                    

Human Colon Carcinoma Growth Delay Assay. Human colon carcinoma cellsare seeded into 96-well tissue culture plates in a final volume of 180μL of 10% fetal bovine serum containing growth media and allowed toincubate overnight (37° C., 5% CO₂, 95% air). Cells of the SW-620 cellline are seeded at 1.0-1.5×10⁴ cells per well. Cells of the HCT-8 andHT-29 cell lines are seeded at 2-4×10³ cells per well. Serially diluteddrug solutions are prepared in growth medium at 10 times concentration;20 μL of these solutions are added to duplicate wells and incubated withthe cells for 3 days in a cell culture incubator. At the end of theincubation period, cells are fixed with 100 μL per well of 10%trichloroacetic acid after removing the drug/culture medium. The platesare washed five times with tap water and stained with 100 μL per well of0.075% sulfrhodamine B in 1% acetic acid for 10 minutes. The plates arerinsed four times and allowed to air dry. The stain in the wells aresolubilized by the addition of 10 mM unbuffered Tris base and theabsorbance read using a microtiter plate optical reader. Inhibition ofcell growth is calculated from absorbance data of the treated cellscompared to untreated control cells.

Human Colon Carcinoma Clonozenic Assay. Human colon carcinoma cells areseeded into 6 well plates in volumes of 3 mL and allowed to incubateovernight (37° C., 5% CO₂, 95% air). SW-620 cells are seeded at 7×10⁵per well; HCT-8 cells are seeded at 5×10⁵ per well; HT-29 cells areseeded at 4×10⁵ cells per well. Serially diluted drugs are prepared at200 times the final concentration, and 15 μL are added to each ofduplicate wells. Cells are incubated with drug for 2 days, rinsed oncewith 1 mL of trypsin+EDTA, and then trypsinized with the same trypsinsolution. After trituration and centrifugation at 750×g for 3 minutes,the cells are suspended in serum-free growth medium and counted using anelectronic particle counter. An agarose mixture appropriate for thecloning of each cell line is made using 10% fetal bovine serum in growthmedium (SW-620-0.35% agarose, HCT-8 and HT-29-0.4% agarose). Anappropriate volume of medium containing the drug treated cells issuspended into the agarose-serum mixture to give final cellconcentrations in 2.5 mL of 1.75×10⁴ SW-620, 1.25×10⁴ HCT-8, and 7.5×10³HT-29. One; milliliter of each of these cell suspensions is added toduplicate wells of 6 well plates previously prepared with 10%serum/growth medium/1% agarose plugs. The cells in these plates areincubated for approximately 2 weeks in the incubator and stained with 1mL per well of 1 mg/mL iodonitrotetrazolium violet stain. The visiblecolonies are counted with an electronic optical colony counter and theclonogenicity of treated cells calculated in comparison to untreatedcontrol cells.

                  TABLE 3                                                         ______________________________________                                        Inhibition of Human Colon Carcinoma Cell Line Growth                                IC.sub.50 (μM)                                                             HCT-8    SW-620  HT-29 HCT-8  SW-620                                                                              HT-29                                 Ex- Growth Growth Growth Clono- Clono- Clono-                                 ample Delay Delay Delay genic genic genic                                   ______________________________________                                        F     2.3      7.2     1.5   >5     >5    >5                                    H 2.8 5.2 2.2 >5 ND >5                                                        P 2.8 6.7 0.8 >5 ND >5                                                        S 5.2 6.8 0.9 ND 2.8 ND                                                     ______________________________________                                         ND = Not determined.                                                     

The compounds of this invention are inhibitors of cyclin-dependentkinases, and accordingly, are useful in treating and preventingatherosclerosis, and other cell proliferative disorders like cancer. Thecompounds have exhibited inhibitory activity against a wide variety ofcyclin-dependent kinases, all in assay systems routinely utilized tomeasure such activity.

Cyclin-Dependent Kinase 4 (cdk4/cyclinD) Assay

Enzyme assays for IC₅₀ determinations and kinetic evaluation wereperformed in 96-well filter plates (Millipore MADVN6550). The totalvolume was 0.1 mL containing a final concentration of 20 mM TRIS(tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM NaCl, 1 mMdithiothreitol, 10 mM MgCl₂, 25 μM ATP containing 0.25 μCi of [³² P]ATP,20 ng of cdk4/cyclinD, 1 μg of retinoblastoma, and appropriate dilutionsof a compound of the present invention. All components except the ATPwere added to the wells, and the plate was placed on a plate mixer for 2minutes. The reaction was started by adding [³² P]ATP and the plate wasincubated at 25° C. for 15 minutes. The reaction was terminated byaddition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate was keptat 4° C. for at least 1 hour to allow the substrate to precipitate. Thewells were then washed 5 times with 0.2 mL of 10% TCA and ³² Pincorporation was determined with a beta plate counter (Wallace Inc.,Gaithersburg, Md.).

Cyclin-Dependent Kinase Assays (cdk2/cyclinE, cdk2/cyclinA,cdkl/cyclinB)

Enzyme assays for IC₅₀ determinations and kinetic evaluation wereperformed in a 96-well filter plate (Millipore MADVN6550) in a totalvolume of 0.1 mL of 20 mM TRIS (tris[hydroxymethyl]aminomethane), at pH7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl₂, 12 mM ATP containing0.25 μCi of [³² P]ATP, 20 ng of enzyme (either cdk2/cyclinE,cdk2/cyclinA, or cdk1/cyclinB), 1 μg retinoblastoma, and appropriatedilutions of the particular invention compound. All components exceptthe ATP were added to the wells, and the plate was placed on a platemixer for 2 minutes. The reaction was begun by addition of [³² P]ATP,and the plate was incubated at 25° C. for 15 minutes. The reaction wasterminated by addition of 0.1 mL of 20% TCA. The plate was kept at 4° C.for least 1 hour to allow the substrate to precipitate. The wells werethen washed 5 times with 0.2 mL of 10% TCA and ³² P incorporationdetermined with a beta plate counter (Wallace Inc., Gaithersburg, Md.).

The results of these cell cycle (CDK) assays are shown in Table 4 below.

                  TABLE 4                                                         ______________________________________                                        Ex-  CDK4/cyclinD                                                                             CDK2/cyclinE                                                                             CDK2/cyclinA                                                                           CDK1/cyclinB                                am- IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50                                   ple μM μM μM μM                                                 ______________________________________                                        W    4.2        1.1        0.88     1.9                                         X 2.6 1.3 0.83 1.5                                                            Y 0.35 5.8 3.5  7.4                                                           Z 1.35 3.0 1.4  4.0                                                           AA 1.5 5.0 ND ND                                                            ______________________________________                                         ND = Not determined.                                                     

What is claimed is:
 1. A compound having the Formula I ##STR22## wherein-- -- -- is absent or bond;R¹ is ##STR23## R² is C₁ -C₆ alkyl, C₃ -C₈cycloalkyl, or C₅ -C₁₂ bicycloalkyl; each R³ is independently hydrogenor C₁ -C₆ alkyl; each n is independently 0 to 7; ##STR24## R⁵ ishydrogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl,and the pharmaceutically accepted salts thereof.
 2. A compound accordingto claim 1 wherein ##STR25##
 3. A compound according to claim 1 whereinand R⁴ is --O(CH₂)_(n) --X.
 4. A compound according to claim 1 wherein##STR26##
 5. A compound according to claim 1 wherein
 6. A compoundaccording to claim 1 wherein R¹ is
 7. A compound according to claim 1wherein R¹ is --NH--(CH₂)_(n) --N(CH₂ CH₃)₂.
 8. A compound according toclaim 1 wherein R⁵ is phenyl or substituted phenyl.
 9. A compoundaccording to claim 1 wherein R⁵ is 2,6-dichlorophenyl.
 10. A compoundaccording to claim 1 wherein R² is methyl.
 11. A compound according toclaim 1 wherein R⁵ is 2,6-dichlorophenyl and R² is methyl.
 12. Thecompounds:7-amino-3-(2,6-dichlorophenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-dimethylamino-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[2-(diethylamino)ethylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[3-(diethylamino)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[4-(diethylamino)butylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[5-(diethylamino)pentylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-methylpiperazin-1-yl)butylamino]-1H-[1,6]naphthyridin-2-one; and3-(2,6-dichlorophenyl)-1-methyl-7-[5-(4-methylpiperazin-1-yl)pentylamino]-1H-[1,6]naphthyridin-2-one.
 13. Thecompounds:3-(2,6-dichlorophenyl)-1-methyl-7-[3-(4-morpholino)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[3-(imidazol-1-yl)propylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-(phenylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[(4-methoxyphenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[(4-(2-(diethylamino)ethoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-[4-(4-morpholino)butylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-7-[(4-(3-(diethylamino)propoxy)phenyl)amino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino]-1H-[1,6]naphthyridin-2-one;and3-(2,6-dichlorophenyl)-1-methyl-7-[(4-(4-methylpiperazin-1-yl)phenyl)amino]-1H-[1,6]naphthyridin-2-one.14. The compounds:7-Amino-1H-[1,6]naphthyridin-2-one;7-Amino-1-ethyl-1H-[1,6]naphthyridin-2-one;7-Fluoro-1-ethyl-1H-[1,6]naphthyridin-2-one; 1-Ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-methoxyphenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and 1-Ethyl-7-phenylamino-3,4-dihydro-1H -[1,6]naphthyridin-2-one. 15.Thecompounds:7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Diethylamino)propoxy)phenylamino]-1-ethyl-1,6-naphthyridin-2-one;1-Ethyl-7-[4-(2-(4-methylpiperazin-1-yl)ethoxy)phenylamino]-1,6-naphthyridin-2-one;1-Ethyl-7-[4-(3-(4-methylpiperazin-1-yl)propoxy)phenylamino]-1,6-naphthyridin-2-one;1-Ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and1-Cyclohexyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.16. Thecompounds:1-Cycloheptyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;and1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one.17. Thecompounds:1-Methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-1H-[1,6]naphthyridin-2-one;7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one; and1-Ethyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one. 18.Thecompounds:1-Isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;7-(4-Fluorophenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;7-(4-Fluorophenylamino)-1-isopropyl-1H-[1,6]naphthyridin-2-one; and7-(4-Fluorophenylamino)-1-isopentyl-1H-[1,6]naphthyridin-2-one.
 19. Thecompounds:1-Cyclopentyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-fluorophenylamino-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and1-Cyclohexyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.20. Thecompounds:1-Cycloheptyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and p11-Bicyclo[2.2.1]hept-2-yl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.21. Thecompounds:1-Methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one1-Cycloheptyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and1-Isopropyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one.22. Thecompounds:1-Isopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and1-Cyclopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one.23. Thecompounds:1-Cyclohexyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Cycloheptyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one.24. Thecompounds:1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]-phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one.25. Thecompounds:1-Ethyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-{4-[4-(3-(Hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-{4-[4-(3-hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one.26. Thecompounds:1-Isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrazol-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-(4-Fluorophenylamino)-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-(4-Fluorophenylamino)-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-(4-Fluorophenylamino)-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Cyclopentyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one.27. Thecompounds:1-Cyclohexyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-fluorophenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(4-(Hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Cycloheptyl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4dihydro-1H-[1,6]naphthyridin-2-one.28. Thecompounds:1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;7-[4-(3-(Hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one.29. Thecompounds:1-Ethyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-[4-(2H-tetrazol-5-yl)phenylamino]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Isopropyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one.30. Thecompounds:1-Isopentyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(piperidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Isopentyl-7-(4-pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;and1-Cyclopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one.31. Thecompounds:1-Cyclohexyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-7-(4-(pyrrolidin-1-yl)phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and1-Cycloheptyl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.32. Thecompounds:1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-methyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopentyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;and3-Fluoro-1-methyl-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one.33. Thecompounds:1-Ethyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopropyl-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-{4-[4-(3-(hydroxy)propyl)piperidin-1-yl]phenylamino}-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-methyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and3-Fluoro-1-isopropyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one.34. Thecompounds:3-Fluoro-1-isopentyl-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(pyrazol-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-(4-fluorophenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-(4-fluorophenylamino)-1-isopropyl-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-(4-fluorophenylamino)-1-isopentyl-1H-[1,6]naphthyridin-2-one;and1-Cyclopentyl-3-fluoro-7-(4-fluorophenylamino-1H-[1,6]naphthyridin-2-one.35. Thecompounds:1-Cyclohexyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-fluorophenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and1-Cycloheptyl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.36. Thecompounds:1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(4-(hydroxy)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopropyl-1H-[1,6]naphthyridin-2-one;3-Fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1-isopentyl-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(3-(hydroxymethyl)piperidin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and3-Fluoro-1-methyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one.37. Thecompounds:1-Ethyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopropyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopentyl-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-[4-(2H-tetrazol-5-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-methyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and3-Fluoro-1-isopropyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one.38. Thecompounds:3-Fluoro-1-isopentyl-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclopentyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cyclohexyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(piperidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-methyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopropyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-Fluoro-1-isopentyl-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;and1-Cyclopentyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one.39. Thecompounds:1-Cyclohexyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Cycloheptyl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;1-Bicyclo[2.2.1]hept-2-yl-3-fluoro-7-(4-(pyrrolidin-1-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-7-(4-fluoro-3-methylphenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-7-(4-ethoxyphenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-7-(3-(hydroxymethyl)phenylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-methyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(2-(morpholin-4-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(2-(piperidin-1-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;and3-(2,6-Dichlorophenyl)-1-methyl-7-[4-(4-(methylpiperazin-1-yl)methyl)phenylamino]-1H-[1,6]naphthyridin-2-one.40. Thecompounds:3-(2,6-Dichlorophenyl)-7-[4-(2-(dimethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]-benzoicacid;3-(2,6-Dichlorophenyl)-7-[3-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;N-(2-{4-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenoxy}ethyl)-N-ethyl-acetamide;{4-[3-(2,6-Dichlorophenyl)-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenyl}-aceticacid; and3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-fluoro-3-methylphenylamino)-1H-[1,6]naphthyridin-2-one.41. Thecompounds:3-(2,6-Dichlorophenyl)-7-(4-ethoxyphenylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-(3-(hydroxymethyl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-(morpholin-4-yl)phenylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(2-(morpholin-4-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(2-(piperidin-1-yl)ethoxy)phenylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(4-(methylpiperazin-1-yl)methyl)phenylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-7-[4-(2-(dimethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;3-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]-benzoicacid;3-(2,6-Dichlorophenyl)-7-[3-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;N-(2-{4-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenoxy}ethyl)-N-ethyl-acetamide;3-(2,6-Dichlorophenyl)-1-ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichlorophenyl)-1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one;and{4-[3-(2,6-Dichlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-ylamino]phenyl}-aceticacid.
 42. Thecompounds:3-(3,5-Dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(3,5-Dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-3-(3,5-dimethoxyphenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-3-(3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(3,5-dimethoxyphenyl)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(3,5-Dimethoxyphenyl)-1-ethyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;3-(3,5-Dimethoxyphenyl)-1-methyl-7-(4-pyridylamino)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;and3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one.43. Thecompounds:3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-1-methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;1-Methyl-3-(2-methyl-3,5-dimethoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2-Chloro-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-1-ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;1-Ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)propylamino]-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2-Chloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-1-methyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;and3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-methyl-1H-[1,6]naphthyridin-2-one.44. Thecompounds:3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;3-(2-Chloro-3,5-dimethoxyphenyl)-7-(4-(diethylamino)butylamino)-1-ethyl-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-1-ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyrdin-2-one;7-(4-(Diethylamino)butylamino)-3-(2,6-dimethyl-3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2-Chloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;3-(2,6-Dimethyl-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-methyl-1H-[1,6]naphthyridin-2-one;3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one;and3-(2-Chloro-3,5-dimethoxyphenyl)-7-[4-(2-(diethylamino)ethoxy)phenylamino]-1-ethyl-1H-[1,6]naphthyridin-2-one.45. Thecompounds:7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(2-methyl-3,5-dimethoxyphenyl)-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-3-(2,6-dimethyl-3,5-dimethoxyphenyl)-1-ethyl-1H-[1,6]naphthyridin-2-one;1-Methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;1-Ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-1-methyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-1-ethyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(2,3,5,6-tetramethylphenyl)-1H-[1,6]naphthyridin-2-one;1-Methyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-phenyl-1H-[1,6]naphthyridin-2-one;and1-Ethyl-7-[3-(4-methylpiperazin-1-yl)propylamino]-3-phenyl-1H-[1,6]naphthyridin-2-one.46. Thecompounds:7-(4-(Diethylamino)butylamino)-1-methyl-3-phenyl-1H-[1,6]naphthyridin-2-one;7-(4-(Diethylamino)butylamino)-1-ethyl-3-phenyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-phenyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-phenyl-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(thiophen-3-yl)-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(thiophen-3-yl)-1H-[1,6]naphthyridin-2-one;7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-methyl-3-(thiophen-2-yl)-1H-[1,6]naphthyridin-2-one;and7-[4-(2-(Diethylamino)ethoxy)phenylamino]-1-ethyl-3-(thiophen-2-yl)-1H-[1,6]naphthyridin-2-one.47. A compound according to claim 1 wherein -- -- -- is absent.
 48. Acompound according to claim 1 wherein -- -- -- is a bond.
 49. A compoundaccording to claim 1 wherein R² is --CH₂ CH₃.
 50. A compound accordingto claim 1 wherein R¹ is ##STR27## wherein aryl is phenyl andsubstituted aryl is substituted phenyl.
 51. A compound according toclaim 1 wherein R² is --CH₃, --CH₂ CH₃, ##STR28##
 52. A compoundaccording to claim 1 wherein R⁵ is hydrogen ##STR29## fluorine,##STR30##
 53. A compound according to claim 1 wherein R¹ is --NH₂,--F,--NH-phenyl, --NH-substituted phenyl, ##STR31##
 54. A compound havingthe Formula I wherein-- -- -- is a bond or absent; R¹ is--NH₂, --F,--NH-phenyl, --NH-substituted phenyl, ##STR32## R² is --CH₃, --CH₂ CH₃,hydrogen, ##STR33## R⁵ is hydrogen ##STR34## fluorine, ##STR35## thepharmaceutically acceptable salts thereof.
 55. A method of treatingcancer, the method comprising administering to a patient having cancer atherapeutically effective amount of a compound of claim
 1. 56. A methodof treating or preventing atherosclerosis, the method comprisingadministering to a patient having atherosclerosis or at risk of havingatherosclerosis a therapeutically effective amount of a compound ofclaim
 1. 57. A method of treating or preventing restenosis, the methodcomprising administering to a patient having restenosis or at risk ofhaving restenosis a therapeutically effective amount of a compound ofclaim
 1. 58. A method of treating psoriasis, the method comprisingadministering to a patient having psoriasis a therapeutically effectiveamount of a compound of claim
 1. 59. A method of inhibiting proteintyrosine kinases, the method comprising administering to a patient inneed of protein tyrosine kinase inhibition a protein tyrosine kinaseinhibiting amount of a compound of claim
 1. 60. The method of claim 59wherein the protein tyrosine kinase is c-Src.
 61. The method of claim 60wherein the protein tyrosine kinase in PDGFr.
 62. The method of claim 60wherein the protein tyrosine kinase is FGFr.
 63. A method of inhibitingall cycle kinases, the method comprising administering to a patient inneed of cell cycle kinase inhibition a cell cycle kinase inhibitingamount of a compound of claim
 1. 64. The method of claim 63 wherein thecell cycle kinase is CDK4, CDK2, or CDK1.
 65. A pharmaceuticalcomposition that comprises a compound of claim 1.